Atrovent®
Ipratropium bromide
Presentation
| Inhaler: | 20 mcg / metered dose, equivalent to 21 mcg as the monohydrate. |
| Inhaler Forte: | 40 mcg / metered dose, equivalent to 42 mcg as the monohydrate. |
| Respule Paediatric: | 250 mcg / 1ml, equivalent to 261 mcg as the monohydrate. 250 mcg / 2ml, equivalent to 261 mcg as the monohydrate. |
| Respule: | 500 mcg / 1ml, equivalent to 522 mcg as the monohydrate. 500 mcg / 2ml, equivalent to 522 mcg as the monohydrate |
Uses
Actions
Atrovent contains ipratropium bromide which 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 for 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.
Pharmacokinetics
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%. 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 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 [47,48]. 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.
Indications
Atrovent is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema and when used concomitantly with inhaled beta-agonists, for asthma.
Dosage and Administration
The following dosages should be regarded as a guide and adjusted to suit the requirements of the individual patient to provide optimal routine maintenance.
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 dyspnoea (difficulty in breathing) a doctor should be consulted immediately.
| Inhaler: 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. |
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| Children: 6-12 years. | Usually 1 or 2 puffs, 3 times daily. |
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| 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.
| Inhaler Forte: Adults | Usually 1 or 2 puffs 3 to 4 times daily. Since a requirement for increasing doses suggests that additional therapeutic modalities may be needed, a total daily dose of 8 puffs should generally not be exceeded. |
Respules: Adults (including elderly) and adolescents over 12 years of age:
| Maintenance Treatment: | 1 respule 3 to 4 times daily |
| Acute Attacks: | 1 respule; repeated doses can be administered until the patient is stable. The time interval between doses may be determined by the physician. |
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| Paediatric Respules: | |
| Children 6 to 12 years: | 1 respule; repeated doses can be administered until the patient is stable. The time interval may be determined by the physician. Daily dosage exceeding 1mg in children under 12 years of age should be given under medical supervision. |
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| Under 6 years of age: | 1 respule; should be given under medical supervision, repeated doses can be administered until the patient is stable. The time interval may be determined by the physician. |
Atrovent respules are commonly used in combination with β2-agonist to maximise bronchodilation.
Atrovent RESPULES can be administered using a range of commercially available nebulising devices. Where wall oxygen is available it is best administered at a flow rate of 6 - 8 litres per minute.
Atrovent Respules and disodium cromoglycate inhalation solutions that contain the preservative benzalkonium chloride should not be administered simultaneously in the same nebuliser as precipitation may occur.
Contraindications
Atrovent metered dose aerosol is contraindicated in patients with a history of hypersensitivity to soya lecithin or related food products such as soybean and peanut. For such patients other Atrovent formulations (solutions for inhalation, Inhalets) without soya lecithin can be used.
Atrovent should also not be taken by patients with known hypersensitivity to atropine or its derivatives or to any other component of the product.
Warnings and Precautions
Atrovent should be used with caution in patients predisposed to narrow-angle glaucoma, or with prostatic 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, as demonstrated by rare cases of urticaria, angio-oedema, rash, bronchospasm, 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, has come into contact with the eyes. Thus patients must be instructed in the correct administration of Atrovent metered aerosol.
Eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival and corneal congestion 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 should be sought immediately.
Patients must be instructed in the correct administration of Atrovent solution for inhalation. Care must be taken not to allow the solution or mist into the eyes. It is recommended that the nebulised solution is administered via a mouth piece. If this is not available and a nebuliser mask is used, it must fit properly. Patients who may be predisposed to glaucoma should be warned specifically to protect their eyes.
Use in Pregnancy
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.
Use in Lactation
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.
Effect on driving or operating machinery
Presumed to be safe or unlikely to produce an effect on the ability to drive or use machinery.
Adverse Effects
The most frequent non-respiratory adverse events reported in clinical trials were headache, nausea and dryness of the mouth.
Because of the low intestinal absorption of Atrovent, anticholinergic side effects, such as increase of heart rate and palpitations, ocular accommodation disturbances, gastro-intestinal 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: Warnings and Precautions).
As with other inhaled therapy including bronchodilators cough, local irritation and, less commonly inhalation induced bronchoconstriction have been observed.
Allergic-type reactions such as skin rash, angio-oedema of the tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions have been reported, with positive rechallenge in some cases. Many of the patients have had a history of allergy to other drugs and/or foods, including soybean (see: Contraindications).
Interactions
Beta-adrenergics and xanthine preparations may intensify the bronchodilator effect.
The risk of acute glaucoma in patients with a history of narrow-angle glaucoma (see Warnings and Precautions) may be increased when nebulised ipratropium bromide and beta-mimetics are administered simultaneously.
Overdosage
No symptoms specific to overdose have been encountered. In view of the wide therapeutic range and topical administration of Atrovent, 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.
Pharmaceutical Precautions
Store in a safe place out of the reach of children.
Store below 25°C
Inhaler
Shake well before use. Do not expose Atrovent Metered Dose Inhaler to high temperatures. Do not force the inhaler open even when apparently empty.
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