1 mL (20 drops) nebuliser solution contains 261mcg (8r)-3α-hydroxy-8-isopropyl-1αH,5αH-tropanium bromide (±)-tropate monohydrate (= ipratropium bromide monohydrate) corresponding to 250 mcg ipratropium bromide anhydrous.
Excipients/Inactive Ingredients: Benzalkonium chloride, disodium edetate dihydrate, sodium chloride, hydrochloric acid, purified water.
Pharmacotherapeutic Group: Anticholinergics. ATC Code: R03BB01.
Pharmacology: ATROVENT (ipratropium bromide) is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In nonclinical studies, it appears to inhibit vagallymediated 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.
Preclinical and clinical evidence suggest no deleterious effect of ATROVENT (ipratropium bromide) on airway mucous secretion, mucociliary clearance or gas exchange.
Clinical trials: In controlled 85 - 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 up to 4 - 6 hours.
The bronchodilator effect of ATROVENT in the treatment of acute bronchospasm associated with asthma has been shown in studies in adults and 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: 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: The drug is minimally (less than 20%) bound to plasma proteins. Nonclinical 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 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.
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: (20 drops = about 1 mL; 1 drop = 0.0125 mg ipratropium bromide anhydrous).
Maintenance treatment: Adults (including elderly) and adolescents over 12 years of age: 2.0 mL (40 drops = 0.5 mg ipratropium bromide anhydrous) 3 to 4 times daily.
Children 6 - 12 years: Because there is limited information in this age group, the following dose recommendation should be given under medical supervision: 1.0 mL (20 drops = 0.25 mg ipratropium bromide anhydrous) 3 to 4 times daily.
Children < 6 years of age: Because there is limited information in this age group the following dose recommendation should be given under medical supervision: 0.4 - 1.0 mL (8 - 20 drops = 0.1 - 0.25 mg ipratropium bromide anhydrous) 3 to 4 times daily.
Acute attacks: Adults (including elderly) and adolescents > 12 years of age: 2.0 mL (40 drops = 0.5 mg ipratropium bromide anhydrous); 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.
Children 6 - 12 years of age: Because there is limited information in this age group, the following dose recommendation should be given under medical supervision: 1.0 mL (20 drops = 0.25 mg ipratropium bromide anhydrous); 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.
Children < 6 years of age: Because there is limited information in this age group the following dose recommendation should be given under medical supervision: 0.4 - 1.0 mL (8 - 20 drops = 0.1 - 0.25 mg ipratropium bromide anhydrous); 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.
Daily doses exceeding 2 mg ipratropium bromide anhydrous in adults and adolescents >12 years of age and 1 mg in children ≤ 12 years of age should be given under medical supervision.
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 solution or mist to enter 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
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.
Local effects: This medicine contains 0.1 mg benzalkonium chloride in each mL.
Benzalkonium chloride may cause wheezing and breathing difficulties. Patients with asthma are at an increased risk for these adverse events.
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.
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. Adverse drug reactions were identified from data obtained in clinical trials and pharmacovigilance during post approval use of the drug.
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.
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.
The risk of acute glaucoma in patients with a history of narrow-angle glaucoma (see Precautions) may be increased when nebulised ipratropium bromide and beta-mimetics are administered simultaneously.
Instructions for use: Read the instructions for use carefully, to ensure correct administration.
The recommended dose is to be diluted with physiological saline to a final volume of 3 - 4 mL and nebulised and inhaled until the solution is consumed. The solution should be rediluted each time before use; any residual diluted solution should be discarded.
Dosage may be dependent upon the mode of inhalation and the quality of nebulisation. The duration of inhalation can be controlled by the dilution volume.
ATROVENT Nebuliser Solution can 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 litres per minute.
ATROVENT Nebuliser Solution is suitable for concurrent inhalation with the Nebuliser Solution of the secretomucolytics ambroxol hydrochloride and bromhexine hydrochloride, or fenoterol hydrobromide.
ATROVENT Nebuliser Solution and disodium cromoglycate Nebuliser Solution should not be administered simultaneously in the same nebuliser as precipitation may occur.
R03BB01 - ipratropium bromide ; Belongs to the class of other inhalants used in the treatment of obstructive airway diseases, anticholinergics.
Inhalation soln 0.025% (clear, colourless or almost colourless liquid, free from suspended particles) x 20 mL x 1's.