ATROVENT USES:Chronic obstructive pulmonary disease (COPD) and chronic asthma If you require a prescription, please visit our online doctor
Therapeutic indications
ATROVENT Inhaler CFC-Free is indicated for the regular treatment of reversible bronchospasm associated with chronic obstructive pulmonary disease (COPD) and chronic asthma.
Go to top of the page4.2 Posology and method of administration
For inhalation use.
Adults (including the elderly):
Usually 1 or 2 puffs three or four times daily, although some patients may need up to 4 puffs at a time to obtain maximum benefit during early treatment.
Children:
6-12 years: Usually 1 or 2 puffs three times daily.
Under 6 years: Usually 1 puff three times daily.
In order to ensure that the inhaler is used correctly, administration should be supervised by an adult.
The recommended dose should not be exceeded.
If therapy does not produce a significant improvement, if the patient's condition gets worse or if a reduced response to treatment becomes apparent, medical advice must be sought. In the case of acute or rapidly worsening dyspnoea (difficulty in breathing) a doctor should be consulted immediately.
Administration
The correct administration of ipratropium bromide from the inhaler is essential for successful therapy. For detailed information on instructions for use please refer to the Patient Information Leaflet.
The canister should be pressed twice to release two metered doses into the air before the inhaler is used for the first time, or when the inhaler has not been used for 3 days or more, to ensure that the inhaler is working properly and that it is ready for use.
Before each occasion on which the inhaler is used the following should be observed:
1. Remove protective cap.
2. Hold the inhaler upright (the arrow on the base of the container should be pointing upwards), breathe out gently and then close the lips over the mouthpiece
3. Breathe in slowly and deeply, pressing the base of the canister firmly at the same time; this releases one metered dose. Hold the breath for 10 seconds or as long as is comfortable, then remove the mouthpiece from the mouth and breathe out slowly.
4. If a second inhalation is required you should wait at least one minute and then repeat Points 2 and 3 above.
5. Replace the protective cap after use.
The inhaler can be used with the Aerochamber Plus™ spacer device. This may be useful for patients, e.g. children, who find it difficult to synchronise breathing in and inhaler actuation.
The canister is not transparent. It is therefore not possible to see when it is empty. The inhaler will deliver 200 actuations. When these have all been used (usually after 3 ' 4 weeks of regular use) the inhaler may still appear to contain a small amount of fluid. However the inhaler should be replaced in order to ensure that each metered dose contains the correct amount of medicine.
WARNING:
The plastic mouthpiece has been specially designed for use with ATROVENT Inhaler CFC-Free to ensure that each metered dose contains the correct amount of medicine. The mouthpiece must never be used with any other metered dose inhaler nor must ATROVENT Inhaler CFC-Free be used with any mouthpiece other than the one supplied with the product.
The mouthpiece should always be kept clean. To clean the mouthpiece, the canister and dustcap must be removed. The mouthpiece should then be washed in warm soapy water, rinsed and dried. Care should be taken to ensure that the small hole in the mouthpiece is flushed through thoroughly. The canister and dustcap should be replaced once the mouthpiece is dry.
Go to top of the page4.3 Contraindications
ATROVENT Inhaler CFC-Free should not be taken by patients with known hypersensitivity to atropine or its derivatives, or to ipratropium bromide or to any other component of the product.
Go to top of the page4.4 Special warnings and precautions for use
When using ATROVENT Inhaler CFC-Free 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.
Caution is advocated in the use of anticholinergic agents in patients predisposed to or with narrow-angle glaucoma, or with prostatic hyperplasia or bladder-outflow obstruction. As patients with cystic fibrosis may be prone to gastrointestinal motility disturbances, ipratropium bromide, as with other anticholinergics, should be used with caution in these patients.
Hypersensitivity reactions following the use of ipratropium bromide have been seen and have presented as urticaria, angioedema, 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 Inhaler CFC-Free and warned against the accidental release of the contents into the eye. Antiglaucoma therapy is effective in the prevention of acute narrow-angle glaucoma in susceptible individuals and patients who may be susceptible to glaucoma should be warned specifically on the need for ocular protection.
Eye pain or discomfort, blurred vision, visual halos or coloured 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.
Patients should be informed when starting treatment that the onset of action of ipratropium bromide is slower than that of inhaled sympathomimetic bronchodilators.
Go to top of the page4.5 Interaction with other medicinal products and other forms of interaction
There is evidence that the administration of ipratropium bromide with beta-adrenergic drugs and xanthine preparations may produce an additive bronchodilatory effect.
Go to top of the page4.6 Pregnancy and lactation
There is no experience of the use of this product in pregnancy and lactation in humans. It should not be used in pregnancy or lactation unless the expected benefits to the mother are thought to outweigh any potential risks to the fetus or neonate.
The safety of ipratropium bromide during human pregnancy has not been established. The benefits of using ipratropium bromide during a confirmed or suspected pregnancy must be weighed against the 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 ipratropium bromide is excreted into breast milk. It is unlikely that ipratropium bromide would reach the infant to an important extent, however caution should be exercised when ipratropium bromide is administered to nursing mothers.
Studies of HFA-134a administered to pregnant and lactating rats and rabbits have not revealed any special hazard.
Go to top of the page4.7 Effects on ability to drive and use machines
On the basis of the pharmacodynamic profile and reported adverse drug reactions it is not likely that ipratropium bromide has an effect on ability to drive and use machines.
Go to top of the page4.8 Undesirable effects
The following side effects have been reported. The frequencies given below are based on clinical trials involving 3250 patients who have been treated with ATROVENT (ipratropium bromide).
Frequencies
Very common: 1/10
Common: 1/100 < 1/10
Uncommon: 1/1,000< 1/100
Rare: 1/10,000 < 1/1,000
Very rare: < 1/10,000
Immune system disorders
Urticaria (1): Uncommon
Anaphylactic reaction: Rare
Angio-oedema of tongue, lips, face: Rare
Nervous system disorders
Headache: Common
Dizziness: Common
Eye disorders
Ocular accommodation disturbances: Uncommon
Angle closure glaucoma(2): Uncommon
Intraocular pressure increased (2): Rare
Eye pain (2): Rare
Mydriasis(2): Rare
Cardiac Disorders
Tachycardia: Uncommon
Palpitations: Rare
Supraventricular tachycardia: Rare
Atrial fibrillation: Rare
Respiratory, Thoracic and Mediastinal Disorders
Cough: Common
Local irritation: Common
Inhalation induced bronchoconstriction(3): Common
Laryngospasm: Rare
Gastro-intestinal Disorders
Dryness of mouth: Common
Vomiting: Common
Gastro-intestinal motility disorder (4): Common
Nausea: Rare
Skin and Subcutaneous Disorders
Skin rash: Uncommon
Pruritus: Uncommon
Renal and Urinary Disorders
Urinary retention (5): Rare
When using ATROVENT Inhaler CFC-Free for the first time some patients may notice that the taste is slightly different from that of the CFC-containing formulation. Some patients have described the taste as unpleasant.
(1) including giant urticaria
(2) ocular complications have been reported when aerolised ipratropium bromide, either alone or in combination with an adrenergic beta2-agonist, has come into contact with the eyes ' see section 4.4.
(3) as with other inhalation therapy, inhalation induced bronchoconstriction may occur with an immediate increase in wheezing after dosing. This should be treated straight away with a fast acting inhaled bronchodilator. ATROVENT Inhaler CFC-Free should be discontinued immediately, the patient assessed and, if necessary, alternative treatment instituted.
(4) e.g. constipation, diarrhoea
(5) the risk of urinary retention may be increased in patients with pre-existing urinary outflow tract obstruction.
Go to top of the page4.9 Overdose
No symptoms specific to overdosage have been encountered. In view of the wide therapeutic window and topical administration of ipratropium bromide, no serious anticholinergic symptoms are to be expected. As with other anticholinergics, dry mouth, visual accommodation disturbances and tachycardia would be the expected symptoms and signs of overdose.
Go to top of the page5. PHARMACOLOGICAL PROPERTIES
Go to top of the page5.1 Pharmacodynamic properties
ATC Code: R03B B01
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.
Ipratropium bromide 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 ipratropium bromide is induced by local drug concentrations sufficient for anticholinergic efficacy at the bronchial smooth muscle and not by systemic drug concentrations.
In clinical trials using metered dose inhalers in patients with reversible bronchospasm associated with asthma or chronic obstructive pulmonary disease significant improvements in pulmonary function (FEV1 increases of 15% or more) occurred within 15 minutes, reached a peak in 1-2 hours, and persisted for approximately 4 hours.
Preclinical and clinical evidence suggest no deleterious effect of ipratropium bromide on airway mucous secretion, mucociliary clearance or gas exchange.
Go to top of the page5.2 Pharmacokinetic properties
The therapeutic effect of ipratropium bromide 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, device and inhalation technique, are generally deposited in the lungs. The major part of the dose is swallowed and passes through the gastrointestinal tract.
Due to the negligible gastrointestinal absorption of ipratropium bromide the bioavailability of the swallowed dose portion is only approximately 2%. 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).
Limited data on total systemic bioavailability (pulmonary and gastrointestinal portions), based on renal excretion (0 ' 24 hours) of ipratropium bromide, suggests a range of 7 to 28% when delivery is via a nebuliser or a MDI product. It is assumed that this is also a valid range for inhalation from the powder preparation. This is also a valid range for 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 distribution 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 (Vβ) 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. A study with radiolabelled material showed that approximately 10% of orally administered ipratropium bromide was absorbed from the gastrointestinal tract and metabolised. Less than 1% of an oral dose is renally excreted as parent compound.
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) is excreted via the biliary-faecal route. The dominant excretion of drug-related radioactivity occurs via the kidneys.
Go to top of the page5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.
Go to top of the page6. PHARMACEUTICAL PARTICULARS
Go to top of the page6.1 List of excipients
1,1,1,2 ' Tetrafluoroethane (HFA-134a)
