SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

ATROVENT Inhaler CFC-Free 20 micrograms/actuation pressurised inhalation solution.

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

One metered dose (ex-valve) contains 20 micrograms ipratropium bromide (as the monohydrate).

For excipients, see 6.1.

3.    PHARMACEUTICAL FORM

Pressurised inhalation, solution.

Each container is filled with 10 ml of a clear, colourless liquid, free from suspended particles.

ATROVENT Inhaler CFC-Free contains a new propellant, HFA-134a, and does not contain any chlorofluorocarbons (CFCs).

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

ATROVENT Inhaler CFC-Free is indicated for the regular treatment of reversible bronchospasm associated with chronic obstructive pulmonary disease (COPD) and chronic asthma.

4.2 Posology and Method of Administration

For inhalation use.

Adults (including the elderly):

Usually 1 or 2 puffs three or four times daily, although some patients may need up to 4 puffs at a time to obtain maximum benefit during early treatment.

Children:

6-12 years:    Usually 1 or 2 puffs three times daily.

Under 6 years:    Usually 1 puff three times daily.

In order to ensure that the inhaler is used correctly, administration should be supervised by an adult.

The recommended dose should not be exceeded.

If therapy does not produce a significant improvement, if the patient’s condition gets worse or if a reduced response to treatment becomes apparent, medical advice must be sought. In the case of acute or rapidly worsening dyspnoea (difficulty in breathing) a doctor should be consulted immediately.

Administration

The correct administration of ipratropium bromide from the inhaler is essential for successful therapy. For detailed information on instructions for use please refer to the Patient Information Leaflet.

The canister should be pressed twice to release two metered doses into the air before the inhaler is used for the first time, or when the inhaler has not been used for 3 days or more, to ensure that the inhaler is working properly and that it is ready for use.

Before each occasion on which the inhaler is used the following should be observed:

1.    Remove protective cap.

2.    Hold the inhaler upright (the arrow on the base of the container should be pointing upwards), breathe out gently and then close the lips over the mouthpiece

3.    Breathe in slowly and deeply, pressing the base of the canister firmly at the same time; this releases one metered dose. Hold the breath for 10 seconds or as long as is comfortable, then remove the mouthpiece from the mouth and breathe out slowly.

4.    If a second inhalation is required you should wait at least one minute and then repeat Points 2 and 3 above.

5.    Replace the protective cap after use.

The inhaler can be used with the Aerochamber Plus™ spacer device. This may be useful for patients, e.g. children, who find it difficult to synchronise breathing in and inhaler actuation.

The canister is not transparent. It is therefore not possible to see when it is empty. The inhaler will deliver 200 actuations. When these have all been used (usually after 3 - 4 weeks of regular use) the inhaler may still appear to contain a small amount of fluid. However the inhaler should be replaced in order to ensure that each metered dose contains the correct amount of medicine.

WARNING:

The plastic mouthpiece has been specially designed for use with ATROVENT Inhaler CFC-Free to ensure that each metered dose contains the correct amount of medicine. The mouthpiece must never be used with any other metered dose inhaler nor must ATROVENT Inhaler CFC-Free be used with any mouthpiece other than the one supplied with the product.

The mouthpiece should always be kept clean. To clean the mouthpiece, the canister and dustcap must be removed. The mouthpiece should then be washed in warm soapy water, rinsed and allowed to air-dry without using any heating system. Care should be taken to ensure that the small hole in the mouthpiece is flushed through thoroughly. The canister and dustcap should be replaced once the mouthpiece is dry.

4.3 Contraindications

ATROVENT Inhaler CFC-Free should not be taken by patients with known hypersensitivity to atropine or its derivatives, or to ipratropium bromide or to any other component of the product.

4.4. Special warnings and precautions for use

When using ATROVENT Inhaler CFC-Free for the first time, some patients may notice that the taste is slightly different from that of the CFC-containing formulation. Patients should be made aware of this when changing from one formulation to the other. They should also be told that the formulations have been shown to be interchangeable for all practical purposes and that the difference in taste has no consequences in terms of the safety or the efficacy of the new formulation.

Hypersensitivity reactions following the use of ipratropium bromide have been seen and have presented as 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 gastrointestinal motility disturbances, ipratropium bromide, as with other anticholinergics, should be used with caution in these patients.

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 into contact with the eyes. Thus patients must be instructed in the correct administration of ATROVENT Inhaler CFC-Free and warned against the accidental release of the contents into the eye. Since the inhaler is applied via mouth piece and manually controlled, the risk for the mist entering the eyes is limited. Antiglaucoma therapy is effective in the prevention of acute narrow-angle glaucoma in susceptible individuals and patients who may be susceptible to glaucoma should be warned specifically on the need for ocular protection.

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 should be informed when starting treatment that the onset of action of ipratropium bromide is slower than that of inhaled sympathomimetic bronchodilators.

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 Inhaler CFC-Free should be discontinued immediately, the patient assessed and, if necessary, alterative treatment instituted.

4.5 Interaction with other medicinal products and other forms of interaction

There is evidence that the administration of ipratropium bromide with beta-adrenergic drugs and xanthine preparations may produce an additive bronchodilatory effect.

4.6    Fertility, pregnancy and lactation

There is no experience of the use of this product in pregnancy and lactation in humans. It should not be used in pregnancy or lactation unless the expected benefits to the mother are thought to outweigh any potential risks to the fetus or neonate.

The safety of ipratropium bromide during human pregnancy has not been established. The benefits of using ipratropium bromide 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 ipratropium bromide is administered to nursing mothers.

Studies of HFA-134a administered to pregnant and lactating rats and rabbits have not revealed any special hazard.

Preclinical studies performed with ipratropium bromide showed no adverse effect on fertility (see section 5.3). Clinical data on fertility are not available for ipratropium bromide.

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.

Renal and Urinary Disorders

Urinary retention⁽³⁾    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 - 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 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.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

No symptoms specific to overdosage have been encountered. In view of the wide therapeutic window and topical administration of ipratropium bromide, 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

ATC Code: R03B B01

Trials with a treatment duration of up to three months involving adult asthmatics and COPD patients, and asthmatic children, in which the HFA formulation and the CFC formulation have been compared have shown the two formulations to be therapeutically equivalent.

Ipratropium bromide 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 ipratropium bromide 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 asthma or 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 ipratropium bromide on airway mucous secretion, mucociliary clearance or gas exchange.

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 mainly metabolised 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

The toxicity of ipratropium bromide has been investigated extensively in the following types of studies: acute, subchronic and chronic toxicity, carcinogenicity, reproductive toxicity and mutagenicity via oral, intravenous, subcutaneous, intranasal and/or inhalation routes. Based on these toxicity studies, the probability of systemic anticholinergic side effects decreases in the following order:

intravenous > subcutaneous > oral > inhalation > intranasal.

Pre-clinically, ipratropium bromide was found to be well-tolerated. Two-year carcinogenicity studies in rats and mice have revealed no carcinogenic activity at doses up to approximately 1,200 times the maximum recommended human daily dose for intranasal ipratropium. Results of various mutagenicity tests were negative.

Studies to investigate the possible influence of ipratropium bromide on fertility, embryo-fetotoxicity, and peri-/postnatal development have been performed on mice, rats and rabbits. High oral levels, i.e. 1000 mg/kg/day in the rat and 125 mg/kg/day in the rabbit were maternotoxic for both species and embryo-/fetotoxic in the rat, where the fetal weight was reduced. Treatment-related malformations were not observed. The highest, technically feasible doses for inhalation of the metered dose aerosol, 1.5 mg/kg/day (human equivalent dose of 0.24 mg/kg/day) in rats and 1.8 mg/kg/day (human equivalent dose of 0.576 mg/kg/day) in rabbits, showed no adverse effects on reproduction.

These doses are 6- and 14-fold the maximum recommended human daily dose (MRHDD) of 2 mg or 0.04 mg/kg (based on a body weight of 50 kg).

6.    PHARMACEUTICAL PARTICULARS

6.1 List of excipients

1,1,1,2 - Tetrafluoroethane (HFA-134a) Ethanol anhydrous Purified water Citric acid anhydrous.

Incompatibilities

Not applicable.

Shelf life

36 months.

6.4 Special precautions for storage

Do not store above 25^oC. Protect from direct sunlight, heat and frost.

The canister contains a pressurised liquid. Do not expose to temperatures higher than 50^oC. Do not pierce the canister.

6.5 Nature and contents of container

17 ml stainless steel pressurised container with a 50 pl metering valve and oral adaptor. Each canister contains 200 actuations.

6.6 Instruction for use, handling and disposal

None.

7    MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim Limited

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 00015/0266

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/12/2005

10    DATE OF REVISION OF THE TEXT

03/02/2015