Atrovent^® 250 UDVs^®, 1 ml

Atrovent^® UDVs^®, 2 ml

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.

Nebuliser solution.

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.

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.

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

Use of the nebuliser solution should be subject to close medical supervision during initial dosing.

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 gastro-intestinal motility disturbances, ATROVENT, as with other anticholinergics, should be used with caution in these patients.

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

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.

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.

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.

None stated.

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).

⁽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 during nebuliser therapy– see section 4.4.

⁽³⁾ e.g. constipation, diarrhoea

⁽⁴⁾ 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 disturbances 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 cyclic guanosine monophosphate (cyclic GMP) caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle.

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.

The therapeutic effect of ATROVENT 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 gastro-intestinal tract.

Due to the negligible gastro-intestinal 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 gastro-intestinal portions), based on renal excretion (0 – 24 hours) of ipratropium bromide, suggests a range of 7 – 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.

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 (V_β) 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 gastro-intestinal 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.

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

1N Hydrochloric Acid

Purified Water

Not applicable.

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.

Do not store above 25ºC. Keep vials in the outer carton.

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

None.

Boehringer Ingelheim Limited

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

PL 0015/0108

27 August 1986 / 23 December 2005

June 2009

Prescription Only Medicine