Class: Respiratory System
Dosage Form: Ampoules
Description: Muscarinic antagonist, bronchodilator
Manufacturer: Boehringer Ingelheim
1 unit dose vial (2 ml) solution for inhalation contains:
Ipratropium bromide………….200, 500 mcg
Atrovent is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In preclinical studies, it appears to inhibit vagally mediated reflexes by antagonizing 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.
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 bronchitis 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 gastrointesitnal tract.
Due to the negligiblle gastrointestinal absorption of ipratropium bromide the bioavailability of the swallowed dose portion accounts 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 gastrointestinal portions) of inhaled doses of ipratropium bromide was estimated to be in the range of 7% to 28%. It is assumed that this is also a valid range for the inhalation from the solution for inhalation preparation.
Kinetic parameters describing the disposition of ipratropium bromide were calculated from plasma concentrations after IV administration.
A rapid biphasic decline in plasma concentrations is observed. The Vd is 338 litres. The drug is minimally (less than 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 gastrointestinal tract)
In excretion balance studies, after intravenous administration of a radioactive dose less than 19% of the drug-related radioactivity (including parent compound and all metabolites) are excreted via the biliary-fecal 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 and emphysema.
Atrovent is indicated, when used concomitantly with inhaled beta-agonists in the treatment of acute bronchospasm associated with chronic obstructive pulmonary disease including chronic bronchitis and asthma.
Atrovent is contraindicated in patients with known hypersensitivity to atropine or its derivatives or to any other component of the product.
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. Atrovent and disodium cromoglycate inhalation solutions should not be simultaneously administered in the same nebulizer as precipitation may occur.
The most frequently non-respiratory adverse events in clinical trials were headache, nausea, and dryness of mouth. Because of the low systemic absorption of Atrovent (ipratropium bromide), anticholinergic side effects, such as tachycardia and palpitations, ocular accommodation disturbances, gastrointestinal motility disturbances and urinary retention are rare and reversible, although the risk of urinary retention may be increased in patients with pre-existing outflow tract obstruction. Ocular side effects have been reported (see “Special Precautions”). As with other inhaled therapy including bronchodilators, cough, and less common, paradoxical bronchoconstriction has been observed.
Dosage and Administration:
The dosage should be adapted to the individual requirements of the patient; patients should also be kept under medical supervision during treatment. Unless otherwise prescribed, the following doses are recommended:
1. Children 6-12 Years:
- 1 unit dose vial (UDV); repeated doses can be administered until the patient is stable
- The time interval between the doses may be determined by the physician
- Atrovent can be administered combined with an inhaled beta-agonist
2. Children Under 6 Years of Age:
Because there is limited information in this age group the following dose recommendation should be given under medical supervision:
- 1 unit dose vial; repeated doses can be administered until the patient is stable. The time interval between the doses may be determined by the physician
- Atrovent can be administered combined with an inhaled beta-agonist
3. Acute attacks:
- Adults (including elderly) and adolescents over 12 years of age: 1 unit dose vial; repeated doses can be administered until the patient is stable. The time interval between the doses may be determined by the physician
4. Maintenance treatment:
- Adults (including elderly) and adolescents over 12 years of age: 1 unit dose vial, 3 to 4 times daily
Atrovent can be administered combined with an inhaled beta-agonist.
The unit dose vials of 2 ml are to be diluted with physiological saline up to a final volume of 2-4 ml or may be combined with Berotec inhalation solution. Daily doses exceeding 2 mg in adults and children over 12 years of age should be given under medical supervision. It is advisable not to greatly exceed the recommended daily dose during either acute or maintenance treatment.
If therapy dose not produce a significant improvement or of the patient’s condition gets worse, medical advise 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. Atrovent inhalation solution ca be administered using a range of commercially available nebulising devices. Where wall oxygen is available, the solution is best administered at a flow rate of 6-8 liters per minute.
Atrovent inhalation solution is suitable for concurrent administration with the secretomucolytics, Mucosolvan, inhalation solution and Bisolvon, and Berotec inhalation solutions.
Atrovent UDVs and disodium cromoglycate inhalation solutions that contain the preservative benzalkonium chloride should not be administered simultaneously in the same nebulizer as precipitation may occur.
Since the unit dose vials contain no preservative, it is important that the contents are used soon after opening and that a fresh vial is used for each administration to avoid microbial contamination.
Partly used, opened or damaged unit dose vials should be discarded.
The symptoms specific to overdosage have been encountered. In view of the wide therapeutic range and topical administration of Atrovent inhalation solution, no serious anticholinergic symptoms are to be expected. Minor systemic manifestations of anticholinergic action, including dry mouth, visual accommodation disturbances and tachycardia may occur.
Pregnancy and Lactation:
Although preclinical studies have shown no hazard, safety during human pregnancy is not established. The usual precautions regarding the use of drugs in pregnancy, especially during the first trimester should be observed.
It is not known whether Atrovent is excreted in breast milk. Although lipid-insoluble quaternary base pass into breast milk, it is unlikely that Atrovent would reach the infant to an important extent, especially when taken by inhalation solution. However, because many drugs are excreted in breast milk, caution should be exercised when Atrovent is administered in a nursing woman.
There have been isolated reports of ocular complications (i.e. mydriasis, increase intraocular pressure, angle-closure glaucoma, eye pain) when aero-solized ipratropium bromide either alone or in combination with an adrenergic beta2-agonist, has escaped into the eyes. Eye pain or discomfort, blurred vision, visual halos or colored images in associated with red eyes from conjunctival and corneal congestion may be signs of acute angle-closure glaucoma. Should any combination of these symptoms develop, treatment with miotic drops should be initiated and specialist advice sought immediately.
Patients must be instructed in the correct administration of Atrovent inhalation solution. Care must be taken not to allow the solution or mist into the eyes. It is recommended that the nebulized solution be administered via a mouth piece. If this is not available and a nebulizer mask is used, it must fit properly. Patients who may be predisposed to glaucoma should be warned specifically to protect their eyes. Atrovent should be used with caution in patients predisposed to narrow-angle glaucoma, or with prostatic hypertrophy or bladder-neck obstruction. Patients with cystic fibrosis may be more prone to gastrointestinal motility disturbances. Immediate hypersensitivity reactions may occur after administration of Atrovent inhalation solution, as demonstrated by care cases of urticaria, angioedema, rash, bronchospasm and oropharyngeal edema.
Available in solution for inhalation in unit dose vials in packs of 2 strips of 10 vials.
Store at room temperature, below 25°C.