Clear, colourless liquid, free from suspended particles.
1 metered dose (puff) contains 21 mcg (8r)-3α-hydroxy-8-isopropyl-1αH,5αH-tropanium bromide (±)-tropate monohydrate (= ipratropium bromide monohydrate) corresponding to 20mcg ipratropium bromide anhydrous.
Excipients/Inactive Ingredients: Propellant: 1,1,1,2-Tetrafluoroethane (HFA [hydrofluoralkane] 134a).
Other excipients: citric acid anhydrous, water purified, ethanol anhydrous, nitrogen (inert gas).
Pharmacotherapeutic group: Anticholinergics. ATC Code: R03BB01.
Pharmacology: Mode of action: Atrovent (ipratropium bromide) is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In non-clinical 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 Ca++ which is caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle.
Ca++ release is mediated by the second messenger system consisting of IP3 (inositol triphosphate) and DAG (diacylglycerol).
The bronchodilation following inhalation of Atrovent (ipratropium bromide) is primarily local and site specific to the lung and not systemic in nature.
Non-clinical and clinical evidence suggest no deleterious effect of Atrovent (ipratropium bromide) on airway mucous secretion, mucociliary clearance or gas exchange.
Clinical trials: 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.
In controlled 90 day studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (chronic bronchitis and emphysema) significant improvements in pulmonary function occurred within 15 minutes, reached a peak in 1-2 hours, and persisted for up to 4 - 6 hours.
In controlled 90 day studies in patients with bronchospasm associated with asthma, significant improvements in pulmonary function (FEV1 increases of 15%) occurred in 54% of the patients.
Pharmacokinetics: Absorption: The therapeutic effect of ATROVENT is produced by a local action in the airways. Time courses of bronchodilation and systemic pharmacokinetics do not run in parallel.
Following inhalation 10 to 30% of a dose is generally deposited in the lungs, depending on the formulation and inhalation technique. The major part of the dose is swallowed and passes the gastro-intestinal tract.
The portion of the dose deposited in the lungs reaches the circulation rapidly (within minutes).
Cumulative renal excretion (0-24 hrs) of the parent compound is approximated to 46% of an intravenously administered dose, below 1% of an oral dose and approximately 3 to 13% of an inhaled dose. Based on these data the total systemic bioavailability of oral and inhaled doses of ipratropium bromide is estimated at 2% and 7 to 28% respectively.
Taking this into account, swallowed dose portions of ipratropium bromide do not relevantly contribute to systemic exposure.
Distribution: Kinetic parameters describing the disposition of ipratropium were calculated from plasma concentrations after i.v. administration. A rapid biphasic decline in plasma concentrations is observed. The apparent volume of distribution at steady-state (Vdss) is approximately 176 L (≈ 2.4 L/kg). The drug is minimally (less than 20%) bound to plasma proteins. Non-clinical data indicate that quaternary amine ipratropium does not cross the placental or the blood-brain barrier. The known metabolites show very little or no affinity for the muscarinic receptor and have to be regarded as ineffective.
Biotransformation: After intravenous administration approximately 60% of a dose is metabolised, mainly by conjugation (40%), whereas after inhalation about 70% of the systemically available dose is metabolised by ester hydrolysis (41%) and conjugation (36%).
The known metabolites, are formed by hydrolysis, dehydration or elimination of the hydroxy-methyl group in the tropic acid moiety.
Elimination: Ipratropium has a total clearance of 2.3 L/min and a renal clearance of 0.9 L/min.
In an excretion balance study cumulative renal excretion (6 days) of drug-related radioactivity (including parent compound and all metabolites) accounted for 72.1% after intravenous administration, 9.3% after oral administration and 3.2% after inhalation. Total radioactivity excreted via the faeces was 6.3% following intravenous application, 88.5% following oral dosing and 69.4% after inhalation. Regarding the excretion of drug-related radioactivity after intravenous administration, the main excretion occurs via the kidneys. The half-life for elimination of drug-related radioactivity (parent compound and metabolites) is 3.6 hours.
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 and the patients should be kept under medical supervision during treatment. It is advisable not to exceed the recommended daily dose during either acute or maintenance treatment.
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. The patient should be instructed that in the case of acute or rapidly worsening dyspnoea physician should be consulted immediately.
The following dosages are recommended: Maintenance treatment: Adults and children > 6 years of age: 2 metered doses (puffs) 4 times daily.
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.
For acute exacerbations of chronic obstructive pulmonary disease treatment with ATROVENT nebuliser solution may be indicated.
Because of insufficient information in children ATROVENT metered dose aerosol should only be used on medical advice and under the supervision of an adult.
Instructions for use: Please read the instructions for use carefully, to ensure correct administration.
The correct administration is essential for successful therapy.
Before first time use: Depress the valve twice before the inhaler is used.
Before each use the following rules should be observed: 1. Remove protective cap.
2. Breathe out deeply.
3. Hold the inhaler and close lips over the mouthpiece. The arrow and the base of the container should be pointing upwards.
4. Breathe in as deeply as possible, pressing the base of the canister firmly at the same time, this releases one metered dose. Hold the breath for a few seconds, then remove the mouthpiece and breathe out. The same action should be repeated for a second inhalation.
5. Replace the protective cap after use.
6. After not using the inhaler for three days, the valve has to be actuated once.
The container is not transparent. It is therefore not possible to see when it is empty. The inhaler will deliver 200 puffs. When the labelled number of doses have been used (usually after 3 weeks when used as recommended), the canister may still appear to contain a small amount of fluid. The inhaler should, however, be replaced so that patient can be certain in getting the right amount of medicine in each actuation.
Clean the mouthpiece at least once a week. It is important to keep the mouthpiece of the inhaler clean to ensure that medicine does not build up and block the spray.
For cleaning, first take off the dust cap and remove the canister from the mouthpiece.
Rinse warm water through the mouthpiece until no medication build-up and/or dirt is visible.
After cleaning shake out the mouthpiece and let it air-dry without using any heating system. Once the mouthpiece is dry, replace the canister and the dust cap.
WARNING: The plastic mouthpiece has been specially designed for use with ATROVENT metered dose inhaler to ensure that patient always get the right amount of the medicine. The mouthpiece must never be used with any other metered dose inhaler nor must the ATROVENT metered dose inhaler 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 50°C.
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 disorder and increase of heart rate may occur.
ATROVENT is contraindicated in patients with known hypersensitivity to atropine or its derivatives (such as the active substance ipratropium bromide) or to any other component of the product.
Hypersensitivity: Immediate hypersensitivity reactions may occur after administration of ATROVENT, as demonstrated by rare cases of rash, urticaria, angioedema, oropharyngeal oedema bronchospasm and anaphylaxis.
Paradoxical bronchospasm: As with other inhaled medicines ATROVENT may result in paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs ATROVENT should be discontinued immediately and substituted with an alternative therapy.
Ocular complications: ATROVENT should be used with caution in patients predisposed to narrow-angle glaucoma.
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 in contact with the eyes.
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 must be instructed in the correct administration of ATROVENT: Care must be taken not to allow the mist to enter into the eyes. Since the metered dose inhaler is applied via mouthpiece and manually controlled, the risk for the mist entering the eyes is limited.
Renal and urinary effects: ATROVENT should be used with caution in patients with pre-existing urinary outflow tract obstruction (e.g. prostatic hyperplasia or bladder-neck obstruction).
Gastro-intestinal motility disturbances: Patients with cystic fibrosis may be more prone to gastro-intestinal motility disturbances.
ATROVENT 20 mcg/puff Metered Dose Inhaler contains ethanol: This medicine contains about 8 mg of alcohol (ethanol) in each actuation.
The amount in each actuation of this medicine is equivalent to less than 1 ml beer or 1 ml wine.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. However, patients should be advised that they may experience undesirable effects such as dizziness, accommodation disorder, mydriasis and blurred vision during treatment with ATROVENT. Therefore, caution should be recommended when driving a car or operating machinery.
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. Nonclinical studies have shown no embryotoxic or teratogenic effects following inhalation or intranasal application at doses considerably higher than those recommended in man.
Lactation: It is not known whether ipratropium bromide is excreted into breast milk. But it is unlikely that ipratropium bromide would reach the infant to an important extent, especially when administered by inhalation. However, caution should be exercised when ATROVENT is administered to nursing mothers.
Fertility: Clinical data on fertility are not available for ipratropium bromide. Non-clinical studies performed with ipratropium bromide showed no adverse effect on fertility.
Many of the listed undesirable effects can be assigned to the anticholinergic properties of ATROVENT. As with all inhalation therapy ATROVENT may show symptoms of local irritation.
Summary of the safety profile: The most frequent side effects reported in clinical trials were headache, throat irritation, cough, dry mouth, gastro-intestinal motility disorders (including constipation, diarrhoea and vomiting), nausea, and dizziness.
List of adverse reactions: The following adverse reactions have been reported during use of ATROVENT in clinical trials and during the post-marketing experience.
Immune system disorders: hypersensitivity, anaphylactic reaction.
Nervous system disorders: headache, dizziness.
Eye disorders: vision blurred, mydriasis, intraocular pressure increased, glaucoma, eye pain, halo vision, conjunctival hyperaemia, corneal oedema, accommodation disorder.
Cardiac disorders: palpitations, supraventricular tachycardia, atrial fibrillation, heart rate increased.
Respiratory, thoracic and mediastinal disorders: throat irritation, cough, bronchospasm, bronchospasm paradoxical, laryngospasm, pharyngeal oedema, dry throat.
Gastrointestinal disorders: dry mouth, nausea, gastrointestinal motility disorder, diarrhoea, constipation, vomiting, stomatitis, oedema mouth.
Skin and subcutaneous tissue disorders: rash, pruritus, angioedema, urticaria.
Renal and urinary disorders: urinary retention.
The chronic co-administration of ATROVENT inhalation with other anticholinergic drugs has not been studied. Therefore, the chronic co-administration of ATROVENT with other anticholinergic drugs is not recommended.
Beta-adrenergics and xanthine preparations may intensify the bronchodilatory effect.
R03BB01 - ipratropium bromide ; Belongs to the class of other inhalants used in the treatment of obstructive airway diseases, anticholinergics.
Atrovent N MDI 20 mcg/dose
200 metered dose x 1's
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