1. Name Of The Medicinal Product
Atrovent® 250 UDVs®, 1 ml
Atrovent® UDVs®, 2 ml
2. Qualitative And Quantitative Composition
Each single dose unit contains 0.025 % w/v ipratropium bromide i.e. 250 micrograms in 1 ml and 500 micrograms in 2 ml.
For excipients, see 6.1.
3. Pharmaceutical Form
Nebuliser solution.
4. Clinical Particulars
4.1 Therapeutic Indications
ATROVENT UDVs are indicated for treatment of reversible bronchospasm associated with chronic obstructive pulmonary disease (COPD).
ATROVENT UDVs are indicated, when used concomitantly with inhaled beta2-agonists, for treatment of reversible airways obstruction as in acute and chronic asthma.
4.2 Posology And Method Of Administration
The dosage should be adapted to the individual needs of the patient. In children aged 12 years and under, only ATROVENT 250 UDVs, 1 ml should be used. The following doses are recommended:
Adults (including the elderly) and children over 12 years of age:
250 - 500 micrograms (i.e. one vial of 250 micrograms in 1 ml or 1 vial of 500 micrograms in 2 ml) 3 to 4 times daily.
For treatment of acute bronchospasm, 500 micrograms.
Repeated doses can be administered until the patient is stable. The time interval between the doses may be determined by the physician.
It is advisable not to exceed the recommended daily dose during either acute or maintenance treatment. Daily doses exceeding 2 mg in adults and children over 12 years of age should only be given under medical supervision.
Children 6 - 12 years of age:
250 micrograms (i.e. one vial of 250 micrograms in 1ml) up to a total daily dose of 1mg (4 vials).
The time interval between doses may be determined by the physician.
Children 0 – 5 years of age (for treatment of acute asthma only):
125 – 250 micrograms (i.e. half to one vial of 250 micrograms in 1 ml) up to a total daily dose of 1 mg (4 vials).
Ipratropium bromide should be administered no more frequently than 6 hourly in children under 5 years of age.
For acute bronchospasm, repeated doses may be administered until the patient is stable.
If therapy does not produce a significant improvement or if the patient's condition gets worse, medical advice must be sought. In the case of acute or rapidly worsening dyspnoea (difficulty in breathing) a doctor should be consulted immediately.
ATROVENT UDVs may be combined with a short-acting beta2-agonist in the same nebuliser chamber, for simultaneous administration where co-administration is required. The solution should be used as soon as possible after mixing and any unused solution should be discarded.
ATROVENT UDVs can be administered using a range of commercially available nebulising devices. The dose of nebuliser solution may need to be diluted in order to obtain a final volume suitable for the particular nebuliser being used (usually 2 – 4 ml); if dilution is necessary use only sterile sodium chloride 0.9% solution.
ATROVENT UDVs and disodium cromoglycate inhalation solutions that contain the preservative benzalkonium chloride should not be administered simultaneously in the same nebuliser as precipitation may occur.
The unit dose vials are intended only for inhalation with suitable nebulising devices and should not be taken orally or administered parenterally.
Please refer to the patient information leaflet for instructions on use with a nebuliser.
4.3 Contraindications
Known hypersensitivity to atropine or its derivatives, or to any other component of the product.
4.4 Special Warnings And Precautions For Use
Use of the nebuliser solution should be subject to close medical supervision during initial dosing.
Immediate hypersensitivity reactions following the use of ATROVENT have been demonstrated by cases of urticaria, angioedema, rash, bronchospasm, oropharyngeal oedema and anaphylaxis.
Caution is advocated in the use of anticholinergic agents in patients predisposed to or with narrow-angle glaucoma, or with pre-existing urinary outflow tract obstruction (e.g. prostatic hyperplasia or bladder-outflow obstruction).
As patients with cystic fibrosis may be prone to gastro-intestinal motility disturbances, ATROVENT, as with other anticholinergics, should be used with caution in these patients.
There have been isolated reports of ocular complications (i.e. mydriasis, increased intra-ocular 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 during nebuliser therapy.
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 UDVs. Care must be taken not to allow the solution or mist to enter the eyes. It is recommended that the nebulised solution is administered via a mouthpiece. 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.
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 UDVs should be discontinued immediately, the patient assessed and, if necessary, alternative treatment instituted.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
There is evidence that the administration of ATROVENT with beta-adrenergic drugs and xanthine preparations may produce an additive bronchodilatory effect.
The risk of acute glaucoma in patients with a history of narrow-angle glaucoma (see Special Warnings and Precautions for Use) may be increased when nebulised ipratropium bromide and beta2-agonists are administered simultaneously.
4.6 Pregnancy And Lactation
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 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 ATROVENT is administered to nursing mothers.
4.7 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. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.
4.8 Undesirable Effects
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.
Frequencies
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(1) 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.
(2) 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 UDVs should be discontinued immediately, the patient assessed and, if necessary, alterative treatment instituted.
(3) the risk of urinary retention may be increased in patients with pre-existing urinary outflow tract obstruction.
4.9 Overdose
No symptoms specific to overdosage have been encountered. In view of the wide therapeutic window and topical administration of ATROVENT, 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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
ATROVENT 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 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 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 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 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 adults and children over 6 years of age. In most of these studies ATROVENT was administered in combination with an inhaled beta2-agonist.
5.2 Pharmacokinetic Properties
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, device and inhalation technique. The major part of the dose is swallowed and passes through 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 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 contribute significantly to systemic exposure.
Distribution
The drug is minimally (less than 20%) bound to plasma proteins. The quarternary amine of the ipratropium ion does not cross the blood-brain barrier.
Biotransformation
Ipratropium has a mean total clearance of 2.3 L/min and a renal clearance of 0.9 L/min. After intravenous administration approximately 60% of the dose is metabolised, mainly by conjugation (40%), wheras after inhalation about 77% of the systemically available dose is metabolised by ester hydrolysis (41%) and conjugation (36%).
Elimination
After inhalation of ipratropium bromide either with HFA 134a or CFC propellant, cumulative renal excretion over 24 hours was approximately 12% and 10%, respectively.
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 3.2 hours. The main urinary metabolites bind poorly to the muscarinic receptor and have to be regarded as ineffective.
5.3 Preclinical Safety Data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium Chloride
1N Hydrochloric Acid
Purified Water
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
24 months (unopened).
As the product contains no preservative, a fresh vial should be used for each dose and the vial should be opened immediately before administration. Any solution left in the vial should be discarded.
6.4 Special Precautions For Storage
Do not store above 25°C. Keep vials in the outer carton.
6.5 Nature And Contents Of Container
Polyethylene unit dose vials containing either 1 ml or 2 ml of solution
Pack sizes of 10, 20, 30, 50, 60, 80, 100, 120, 150, 200, 300, 500 and 1000.
Not all pack sizes may be marketed
6.6 Special Precautions For Disposal And Other Handling
None.
7. Marketing Authorisation Holder
Boehringer Ingelheim Limited
Ellesfield Avenue
Bracknell
Berkshire
RG12 8YS
8. Marketing Authorisation Number(S)
PL 0015/0108
9. Date Of First Authorisation/Renewal Of The Authorisation
27 August 1986 / 23 December 2005
10. Date Of Revision Of The Text
July 2011
11. LEGAL CATEGORY
Prescription Only Medicine
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