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Boehringer Ingelheim Limited

The Crescent Building, , Northwood, Santry, Dublin 9,
Telephone: +353 1 295 9620
Fax: : +353 1 816 3642
Medical Information e-mail: Medinfo@dbl.boehringer-ingelheim.com


Summary of Product Characteristics last updated on medicines.ie: 07/12/2015
SPC Atrovent 500 UDVs, 500 micrograms/2ml Nebuliser Solution


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1. NAME OF THE MEDICINAL PRODUCT

Atrovent 500 UDVs, 500 micrograms/2ml Nebuliser Solution


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each single unit dose contains 500 micrograms ipratropium bromide (as ipratropium bromide monohydrate) in 2 ml of solution (0.025% w/v)

For a full list of excipients, see section 6.1.


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3. PHARMACEUTICAL FORM

Nebuliser Solution (nebuliser liquid)

A clear, colourless aqueous solution.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

ATROVENT 500 UDVs, 2ml 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.


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4.2 Posology and method of administration

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

Adults (including the elderly) and adolescents > 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 adolescents > 12 years of age should only be given under medical supervision.

Children < 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 < 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. The patient should be instructed that in the case of acute or rapidly worsening dyspnoea a physician 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.


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4.3 Contraindications

ATROVENT UDVs are 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.


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4.4 Special warnings and precautions for use

Hypersensitivity

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

Caution is advocated in the use of anticholinergic agents in patients predisposed to narrow-angle glaucoma.

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.

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-outflow obstruction).

Gastro-intestinal motility disturbances

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.


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4.5 Interaction with other medicinal products and other forms of interaction

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.

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 section Special warnings and precautions for use) may be increased when nebulised ipratropium bromide and beta2-agonists are administered simultaneously.


4.6 Fertility, pregnancy and lactation

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 the 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. 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.

Fertility

Clinical data on fertility are not available for ipratropium bromide.

Nonclinical studies performed with ipratropium bromide showed no adverse effect on fertility.


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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. Therefore, caution should be recommended when driving a car or operating machinery.


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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

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

Immune system disorders

Hypersensitivity

Uncommon

Anaphylactic reaction

Uncommon

Nervous system disorders

Headache

Common

Dizziness

Common

Eye disorders

Vision blurred

Uncommon

Mydriasis (1)

Uncommon

Intraocular pressure increased (1)

Uncommon

Glaucoma (1)

Uncommon

Eye pain (1)

Uncommon

Halo vision

Uncommon

Conjunctival hyperaemia

Uncommon

Corneal oedema

Uncommon

Accommodation disorder

Rare

Cardiac Disorders

Palpitations

Uncommon

Supraventricular tachycardia

Uncommon

Atrial fibrillation

Rare

Heart rate increased

Rare

Respiratory, Thoracic and Mediastinal Disorders

Throat irritation

Common

Cough

Common

Bronchospasm

Uncommon

Bronchospasm paradoxical

Uncommon

Laryngospasm

Uncommon

Pharyngeal oedema

Uncommon

Dry throat

Uncommon

Gastro-intestinal Disorders

Dry mouth

Common

Nausea

Common

Gastrointestinal motility disorder

Common

Diarrhoea

Uncommon

Constipation

Uncommon

Vomiting

Uncommon

Stomatitis

Uncommon

Oedema mouth

Uncommon

Skin and subcutaneous tissue disorders

Rash

Uncommon

Pruritus

Uncommon

Angioedema

Uncommon

Urticaria

Rare

Renal and Urinary Disorders

Urinary retention(2)

Uncommon

(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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie.


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


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anticholinergics

ATC Code: R03BB01

ATROVENT is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In nonclinical 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 ≥ 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.


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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 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 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. Nonclinical data indicate that the quaternary amine ipratropium does not cross the placental or the blood-brain barrier.

Biotransformation

After intravenous administration approximately 60% of a dose is metabolised probably the major portion in the liver by oxidation.

The known metabolites, which are formed by hydrolysis, dehydration or elimination of the hydroxy-methyl group in the tropic acid moiety, show very little or no affinity for the muscarinic receptor and have to be regarded as ineffective.

Elimination

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.

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.


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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.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Sodium Chloride

Hydrochloric Acid (for pH adjustment)

Purified Water


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6.2 Incompatibilities

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


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6.3 Shelf life

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.


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6.4 Special precautions for storage

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


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6.5 Nature and contents of container

Low-density polyethylene (LDPE) single dose units formed in strips of 10, in pack sizes of 20 and 60. Each single dose unit contains 2 ml of solution.

Not all pack sizes may be marketed.


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6.6 Special precautions for disposal and other handling

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


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7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim Limited

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

United Kingdom


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8. MARKETING AUTHORISATION NUMBER(S)

PA 7/2/4


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 27 September 1985

Date of last renewal: 21 May 2005


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10. DATE OF REVISION OF THE TEXT

December 2015



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Active Ingredients

 
   ipratropium bromide monohydrate