INFORMATION FOR HEALTH PROFESSIONALS
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| 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 |
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.
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.
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.
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 |
| 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.
| 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. |
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. |
| 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.
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.
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.
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.
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.
Presumed to be safe or unlikely to produce an effect on the ability to drive or use machinery.
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 in patients known to be susceptible, ocular accommodation disturbances, gastro-intestinal motility disturbances, nausea and urinary retention. 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 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).
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.
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.
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.
Prescription Medicine
Inhaler 20 mcg dose, 200 metered doses.
Inhaler (Forte) 40 mcg dose, 200 metered doses.
Respule Paediatric 250 mcg / 1ml, and 250 mcg / 2ml, 10 respules
Respule 500 mcg / 1ml, and 500 mcg / 2ml, 20 respules
The correct operation of the metered aerosol apparatus is essential for successful therapy.
When using the aerosol for the first time it should be shaken, the protective cap removed and the valve depressed once or twice to prime the metering valve before initial use.
The correct operation of the metered aerosol apparatus is essential for successful therapy.
The container is under pressure and should on no account be opened by force or exposed to temperatures exceeding 50ºC. As the container is not transparent it is not possible to see when the contents are used up, but shaking the container will show if there is any remaining fluid.
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 mouthpiece should always be kept clean and can be washed in warm water. If soap or detergent is used, the mouthpiece should be thoroughly rinsed in clear water.
Prepare the nebuliser by following the manufacturer's instructions and the advice of your doctor.
As the Respules contain no preservative, it is important that you use the contents as soon as possible after opening to avoid microbial contamination. Partly used, opened or damaged vials should be discarded.
ATROVENT is also available as: ATROVENT NASAL AQUEOUS 20µg/ puff (with a nasal adaptor) for the treatment of allergic, perennial and vasomotor rhinitis when characterised by watery rhinorrhoea.
With the respiratory preparation, even in doses exceeding the normal therapeutic range, there have been no reports of adverse effects on pulmonary secretion or mucociliary clearance. As the surface area of the lung is far greater than that of the nose, the ATROVENT concentration per square centimetre of lung obtained with the respiratory presentations is considerably less than that obtained in the nose.
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.
Studies to investigate the possible influence of ATROVENT on fertility,
embryo-fetotoxicity, and peri-/postnatal development have been performed on
mice, rats and rabbits. Even the highest oral dose levels employed (1000
mg/kg/day in the rat and
125 mg/kg/day in the rabbit, which proved to be maternotoxic and, to some
extent, embryo-/fetotoxic at dosages, far in excess to the human therapeutic
dose, did not induce malformations in the offspring.
BPI No: 0019-05 dated 15.5.03
BPI No.:0012-05 dated 15.5.03
BPI No.:0022-04 dated 15.5.03
BPI No.:0013-04 dated 15.5.03
Boehringer Ingelheim (N.Z.) Limited
P O Box 76-216
Manukau City
Auckland
NEW ZEALAND
Telephone: (09) 262-1356
Facsimile: (09) 262-1462
24 September 2003