INHALVENT 20 MCG/ACTUATION PRESSURISED INHALATION SOLUTION - summary of medicine characteristics

Inhalvent 20 micrograms per actuation pressurised inhalation solution.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One metered dose (ex-valve) contains 21 micrograms of ipratropium bromide monohydrate, corresponding with 20 micrograms of ipratropium bromide. This is equivalent to a delivered dose (ex-actuator) of 17 micrograms ipratropium bromide.

Excipients with known effect: each actuation contains 0.0084 g of ethanol.

For the full list of excipients, see section 6.1.

Pressurised inhalation, solution.

Pressurised stainless steel canister containing a transparent and colourless solution, fitted with a 50 jil metering valve with a transparent polypropylene actuator (with mouthpiece) and a green polypropylene dust cap.

4.1 Therapeutic indications

Inhalvent is a bronchodilator indicated for the symptomatic treatment of reversible bronchospasm in

– Chronic obstructive pulmonary disease (COPD)

– Asthma as alternative to short acting p2-agonists when p2-agonists are not tolerated.

Inhalvent is indicated in children aged 6–12 years, adolescents and adults.

4.2 Posology and method of administration

Posology

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.

Paediatric population

6–12 years:

Usually 1 or 2 puffs three times daily.

Under 6 years:

There is insufficient data on the use of ipratropium bromide in children under 6 years. Inhalvent should only be used on medical advice and under the supervision of an adult.

In general, a daily dose of 12 inhalations 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.

Treatment of acute severe asthma exacerbations

Ipratropium bromide administered by spacer can be added to inhaled short acting bronchodilators in the treatment of an acute severe asthma exacerbations in the home situation. Both bronchodilators should be administered by spacer. For further conditions and further treatment recommendations, please refer to the national guidelines.

Method of administration

For inhalation use.

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.

Inhalvent contains a solution so it is not required to shake the inhaler before its use.

For optimal results, the canister should be at room temperature before use. If the inhaler gets very cold, take the metal canister out of the plastic case and warm it in your hands for at least two minutes before use. Never use anything else to warm it up.

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

1 Remove the protective cap from the mouthpiece (fig. 1).

fig.1

2 Hold the inhaler upright with the base of the canister at the top (fig. 1), put your thumb on the base below the mouthpiece and the index finger/middle finger on the top of the inhaler. Breathe out as far as is comfortable, but do not breathe into the mouthpiece (fig. 2).

fig.2

3 Place the mouthpiece in your mouth between your teeth and close your lips firmly around it but do not bite it.

4 Breathe in slowly and deeply, pressing down on the top of the inhaler firmly at the same time; this releases one metered dose (fig 3).

fig.3

5 Hold your breath for 10 seconds or as long as is comfortable (fig. 4), then remove the mouthpiece from your mouth and breathe out slowly.

fig.4

6 If a second inhalation is required you should wait at least one minute and then repeat steps 2 to 5.

7 After use always replace the mouthpiece cover.

People with weak hands may find it easier to hold the inhaler with both hands, by placing both forefingers on top of the inhaler and both thumbs on the base below the mouthpiece.

The inhaler can be used with the Aerochamber Plus™ spacer device. This may be useful for patients, e.g. children or elderly, who find it difficult to synchronize 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 Inhalvent 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 Inhalvent be used with any mouthpiece other than the one supplied with the product.

Cleaning

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.

It is important to clean the inhaler regularly. Cleaning must be done it at least once a week. Otherwise it may not work properly.

4.3 Contraindi­cations

Hypersensitivity to the active substance ipratropium bromide, to atropine or its derivatives or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

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 Inhalvent 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. Inhalvent 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 ipratropium bromide with beta-adrenergic drugs and xanthine preparations may produce an additive bronchodilatory effect.

4.6 Fertility, Pregnancy and lactation

Pregnancy

There are no data from the use of ipratropium bromide in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Ipratropium bromide should only be used during pregnancy when strictly indicated.

Breast-feeding

It is not known whether ipratropium bromide is excreted into breast milk, however, it is unlikely that ipratropium bromide would reach the infant to an important extent.

Use of ipratropium bromide during breastfeeding can therefore be considered.

Fertility

Animal studies do not indicate an adverse effect of ipratropium bromide on fertility. There are no clinical data.

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 Inhalvent. 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 Inhalvent. As with all inhalation therapy Inhalvent 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.

The adverse reactions based on the MedDRA system organ class and frequencies are listed in the table below. The frequencies are defined as:

Very common (>1/10),

Common      (>1/100 to <1/10),

Uncommon    (>1/1,000 to <1/100),

Rare   (>1/10,000 to <1/1,000),

Very rare      (<1/10,000)

Frequency not known (cannot be estimated from the available data).

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. Inhalvent 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 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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other drugs for obstructive airway diseases, inhalants, anticholinergics

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 a HFA formulation and a 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 Inhalvent 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).

Based on the cumulative renal excretion, 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.

A two-stage pharmacokinetic cross-over study was conducted in healthy volunteers to compare systemic exposure of ipratropium following inhalation of [To be completed nationally] and Atrovent®, with and without AeroChamber Plus® spacer. The 90% CI for Cmax and AUC0-t were within the standard 80–125% range demonstrating equivalence for Ipratropium and Atrovent® with and without use of AeroChamber Plus® spacer. Use of an AeroChamber Plus® spacer increased mean systemic (which equates to pulmonary absorption) bioavailability of ipratropium by 50% in healthy volunteers compared to administration via a pMDI alone.”

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. Volume of distribution is 338L.

Biotransformation

After intravenous administration approximately 60% of the dose is metabolized, mainly by conjugation (40%), whereas after inhalation about 77% of the systemically available dose is metabolized by ester hydrolysis (41%) and conjugation (36%).

Elimination

The pharmacokinetic parameters for the active ingredient are calculated of plasma levels after intravenous administration. Plasma levels of ipratropium bromide showed a rapid decline and a biphasic course. The half-life of the terminal elimination phase was approximately 1.6 hours. The main urinary metabolites bind poorly to the muscarinic receptor and have to be regarded as ineffective. The total clearance of the active substance is 2.3 L / min. About 40% of the clearance is renal (0.9 L / min) and 60% hepatic (1.4 L / min). 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.

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

1,1,1,2-Tetrafluorethane

Ethanol Anhydrous

Purified water

Anhydrous citric acid

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store protected from direct sunlight

Do not freeze.

Do not store above 30°C.

The canister contains a pressurised liquid. Do not expose to temperatures higher than 50°C.

Do not pierce or burn the canister even when it is apparently empty.

6.5 Nature and contents of container

19 ml stainless steel pressurised container equipped with a metering valve of 50 jil and a transparent plastic actuator containing a mouthpiece with a green dust cap.

The metering valve contains aluminium, stainless steel, polyester and EPDM (ethylene propylene diene monomer) polymer.

Each pressurised container contains 200 actuations.

This medicine is available as 1 box containing 1can or as a multipack containing 3 cans (3 boxes of 1 can, bundled together by a plastic foil).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

LABORATORIO ALDO-UNION, S.L.

Baronesa de Malda, 73

08950 Esplugues de Llobregat

Barcelona

8 MARKETING AUTHORISATION NUMBER(S)

PL 18124/0002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

31/08/2021