Boehringer Ingelheim Limited

Atrovent 250 UDVs 250 micrograms/1 ml Nebuliser Solution

Each single dose unit contains 250 micrograms ipratropium bromide (as ipratropium bromide monohydrate) in 1 ml of solution (0.025% w/v).

For a full list of excipients, see section 6.1.

Nebuliser Solution (nebuliser liquid).

A clear, colourless aqueous solution.

ATROVENT 250 UDVs, 1ml are indicated for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease and, when used concomitantly with inhaled beta₂-agonists, for treatment of acute and chronic asthma and acute bronchospasm associated with chronic obstructive pulmonary disease.

The dosage should be adapted to the individual needs of the patient. Unless otherwise prescribed the following doses are recommended:

Adults (including the elderly) and children over 12 years of age:

500 micrograms 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 under 12 years of age:

250 micrograms up to a total daily dose of 1mg.

The time interval between doses may be determined by the physician.

For acute bronchospasm, repeated doses may be administered until the patient is stable. The time interval between doses may be determined by the physician.

It is advisable not to exceed the recommended daily dose. Daily doses exceeding 1mg in this age group should be given under medical supervision.

There is limited information for children under 6 years of age, therefore the recommended dose should only be given under medical supervision.

ATROVENT UDVs can be administered combined with an inhaled beta₂-agonist.

The dose of nebuliser solution may need to be diluted in order to obtain a final volume suitable for the particular nebuliser being used; if dilution is necessary use only sterile sodium chloride 0.9% solution.

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 can be administered using a range of commercially available nebulising devices.

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.

Known hypersensitivity to atropine or its derivatives, or to any other component of the product.

Immediate hypersensitivity reactions following the use of ATROVENT have been demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, oropharyngeal oedema and anaphylaxis.

Caution is advocated in the use of anticholinergic agents in patients predisposed to 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.

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.

There is evidence that the administration of ATROVENT with beta-adrenergic drugs and xanthine preparations may intensify the bronchodilator effect of ATROVENT.

The risk of acute glaucoma in patients with a history of narrow-angle glaucoma (see Special Warnings and Special Precautions for Use) may be increased when nebulised ipratropium bromide and beta₂-agonists are administered simultaneously.

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 ATROVENT is excreted into breast milk. It is unlikely that ATROVENT would reach the infant to an important extent, however caution should be exercised when ATROVENT is administered to nursing mothers.

Preclinical studies performed with ipratropium bromide showed no adverse effect on fertility. Clinical data on fertility are not available for ipratropium bromide.

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. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.

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

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

⁽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 during nebuliser therapy– see section 4.4.

⁽²⁾ the risk of urinary retention may be increased in patients with pre-existing urinary outflow tract obstruction.

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 disorder and tachycardia would be the expected symptoms and signs of overdose.

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 primarily local and site specific to the lung and not systemic in nature.

Preclinical and clinical evidence suggest no deleterious effect of ATROVENT on airway mucous secretion, mucociliary clearance or gas exchange.

In controlled 90 day studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (e.g. chronic bronchitis and emphysema) significant improvements in pulmonary function (FEV₁ and FEF _25-75% increases of 15% or more) occurred within 15 minutes, reached a peak in 1-2 hours, and persisted in the majority of patients up to 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 beta₂-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. Time courses of bronchodilation and systemic pharmacokinetics do not run in parallel.

Following inhalation, 10 to 30% of a dose is generally deposited in 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 relevantly contribute to systemic exposure.

After inhalation of ipratropium bromide either with HFA 134a or CFC propellant, cumulative renal excretion over 24 hours was approximately 12% and 10%, respectively.

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 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. The quarternary amine of the ipratropium ion does not cross the blood-brain barrier.

The half-life of the terminal elimination phase is approximately 1.6 hours.

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 a dose is metabolised probably the major portion in the liver by oxidation.

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. The main urinary metabolites bind poorly to the muscarinic receptor and have to be regarded as ineffective.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Sodium chloride

Hydrochloric acid (for pH adjustment)

Purified water

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Unopened: 2years

Following removal from foil overwrap: 3 months

Once vial opened: Use immediately. Discard any unused portion.

Diluted product:

From a microbiological point of view, unless the method of dilution precludes the risk of microbiological contamination, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user.

Do not store above 25°C. Keep vials in the outer carton in order to protect from light.

Low-density polyethylene (LDPE) single dose units formed in strips of 10 in pack sizes of 20 and 60. Each single dose unit contains 1 ml of solution.

Not all pack sizes may be marketed.

The dose of nebuliser solution may need to be diluted. If dilution is necessary use only sterile sodium chloride 0.9% solution.

Boehringer Ingelheim Limited

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

United Kingdom

PA 7/2/7

Date of first authorisation: 10^th June 1996

Date of last renewal: 21^st May 2005

March 2012