Document: Ipravent pressurised inhalation, solution ENG SmPC change

• Ipravent pressurised inhalation solution SmPC
• Ipravent pressurised inhalation, solution ENG SmPC

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SUMMARY OF PRODUCT CHARACTERISTICS

Ipravent 20 micrograms per actuation pressurised inhalation, solution

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

One metered dose (ex-valve) contains 8.4 mg of ethanol

For the full list of excipients, see section 6.1

Pressurised inhalation, solution

Ipravent is a colourless solution, filled in an aluminum container fitted with a suitable metering valve and a plastic actuator.

Ipravent is indicated for the regular treatment of reversible bronchoconstriction associated with chronic obstructive pulmonary disease (COPD) and chronic asthma in adults.

Dosage should be adjusted according to each individual's needs. It is not advisable to exceed the recommended daily dose for either acute or maintenance therapy.

Posology

For inhalation use.

The following dosage is recommended for the treatment of adults:

Treatment Control: The inhalation technique of revisiting patient's should be checked.

The recommended dose should not be exceeded.

Method of administration

If the Inhaler has been exposed to low temperatures, the patient should take the metal canister out of the plastic case and warm it in their hands for a minimum of two minutes

The correct administration of ipratropium bromide from the inhaler is essential for successful therapy. It is imperative that patient’s inhaler technique should be checked to ensure optimum drug delivery of ipratropium bromide to the lungs from time to time. 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.

On each occasion on which the inhaler is used the following instructions should be followed:

The plastic mouthpiece has been specially designed for use with Ipravent 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 Ipravent be used with any mouthpiece other than the one supplied with the product.

The mouthpiece should always be kept clean (see section 6.6).

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.

Please read the Patient Information Leaflet for appropriate instructions for use/inhalation.

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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Ipravent should not be used by patients with known hypersensitivity to atropine or its derivatives, hyoscyamine and scopolamine.

Immediate hypersensitivity reactions may occur following the use of ipratropium bromide have been seen and have presented as rare cases of urticaria, angioedema, rash, bronchospasm, oropharyngeal oedema and anaphylaxis.

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

Ipravent can cause dry mouth, which in long term treatment can lead to dental and oral mucosal changes. Teeth should be thoroughly cleaned with fluoride toothpaste 2 times daily.

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. reversible accommodation disorder, mydriasis, increased intraocular pressure, narrow-angle glaucoma, eye pain) when aerosolised ipratropium bromide, either alone or in combination with an adrenergic β₂adrenoceptor agonist, has come into contact with the eyes. 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 must be instructed to use the inhaler properly and warned not to let the spray get in eyes. When the inhaler is given through nozzle with manual control of the dosage, the risk of getting the medicine into the eyes is limited. If Ipravent accidentally gets into the eyes, the eyes should be flushed with running water.

As with other inhalation therapy paradoxical bronchospasm may occur. If it occurs, the treatment should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

This medicinal product contains a small amount of ethanol (less than 9.24 mg in one single dose).

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

A few cases have been reported where combination therapy with salbutamol and ipratropium in asthma (nebulizer) has triggered narrow-angle glaucoma. Terbutaline probably interacts in the same way as salbutamol with ipratropium when administered via nebulizer. The combination is discouraged in predisposed patients.

Fertility

Preclinical studies of ipratropium bromide showed no negative effect on fertility. There are no clinical data on fertility for ipratropium bromide.

Pregnancy

There are no data from the use of ipratropium in pregnant women. 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. As a precautionary measure, it is preferable to avoid the use of ipratropium during pregnancy.

Breast-feeding

It is unknown 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.

Ipravent has moderate influence on the 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 Ipravent.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 ofIpravent. As with all inhalation therapy Ipravent may show symptoms of local irritation.

The most frequent side effects known from clinical trials were headache, throat irritation, cough, dry mouth, gastro-intestinal motility disorders (including constipation, diarrhea 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

Not known: frequency cannot be estimated from the available data

Immune system disorder

Hypersensitivity ⁽¹⁾ Uncommon

Anaphylactic reaction Uncommon

Nervous system disorders

Headache Common

Dizziness Common

Eye disorders

Blurred vision Uncommon

Mydriasis ⁽²⁾ Uncommon

lntraocular pressure increased ⁽²⁾ Uncommon

Glaucoma ⁽²⁾ Uncommon

Eye pain ⁽²⁾ Uncommon

Visual disturbances (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

Paradoxical bronchospasm⁽³⁾ Uncommon

Laryngospasm Uncommon

Pharyngeal oedema Uncommon

Dry throat Uncommon

Dyspnea Not known

Nasal dryness and nasal congestion Not known

Gastro-intestinal Disorders

Dry mouth Common

Nausea Common

Gastro-intestinal motility disorder Common

Diarrhoea Uncommon

Constipation Uncommon

Vomiting Uncommon

Stomatitis Uncommon

Mouth edema Uncommon

Unpleasant taste Not known

Skin and subcutaneous tissue disorders

Rash Uncommon

Pruritus Uncommon

Urticaria Rare

Angioedema of tongue, Uncommon

Lips & face

Renal and Urinary Disorders

Urinary retention⁽⁴⁾ Uncommon

Reporting of suspected adverse reactions

Reporting of 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 national reporting system listed in [To be completed nationally]

Toxicity

Limited experience of overdose. Very low oral absorption.

Symptoms

It is conceivable mainly peripheral anticholinergic symptoms such as dry mouth, mydriasis, tachycardia, urinary retention, constipation, headache, dizziness. At massive doses may possibly exhibit central anticholinergic symptoms such as CNS excitation, and hallucinations may occur.

Treatment

Symptomatic treatment. For any central anticholinergic symptoms physostigmine is given for symptomatic relief.

Pharmacotherapeutic group: Anticholinergic, ATC Code: R03B B01

Ipratropium bromide is a quaternary ammonium compound with anti-cholinergic (parasympatholytic) properties. Bronchial muscle tone is affected in contracting direction by parasympathetic nervous system and the in relaxant direction by sympathetic nervous system. The contracting impulses communicated via the vagus nerve. This activity can be reversed with anticholinergics such as ipratropium. 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.

Ipravent would give better effect in chronic bronchitis than in asthma, probably because vagal reflex plays major role in bronchospasm in chronic bronchitis.

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 (FEV, 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. Effect occurs within 15 minutes. Maximum output is reached after 1-2 hours. The duration of action is about 4-6 hours.

Ipravent can be used with beta-adrenergic receptor agonist (see sections 4.4 and 4.5).

Absorption

The therapeutic effect of Ipravent is caused by a local action in the airways. Therefore, there is no progressive relationship between bronchodilation and systemic pharmacokinetics.

Depending on the formulation device and inhalation technique, after inhalation approximately 10 to 30% (13.3 % ± 6.9 % (mean ± SD)) of a dose reaches the lungs. The major part of the dose is swallowed and passes to the body via the gastro-intestinal tract.

The part of the dose that reaches to the lungs reaches the circulation within minutes.

Cumulative renal excretion (0-24 hrs) of parent drug is estimated at 46% of an intravenously administered dose, less than 1% of an oral dose and about 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 kinetic parameters for ipratropium were calculated on the basis of plasma concentrations after intravenous administration. A rapid biphasic decline in plasma concentration can be observed. The apparent volume of distribution at steady state (Vdss) is approximately 176L (2.4L/kg).

The drug is bound to plasma protein to a very small extent (on average 17 ± 4.2 % (mean ± SD)). The quarternary amine ipratropium does not cross the blood-brain barrier.

Biotransformation

Ipratropium has a mean total clearance of 2.3 L / min (SD = ± 0.58%) and a renal clearance of 0.9 L / min. After intravenous administration approximately 59% (SD = ± 7.1%) of the dose is metabolised, most probably by oxidation in the liver.

Elimination

The average terminal half-life is approximately 1.6 hours. After inhalation of ipratropium bromide either with HFA 134a or CFC propellant, cumulative renal excretion over 24 hours was approximately 12% and l0%, respectively.

In a mass 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.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.

Norflurane (1, l, 1, 2 - Tetrafluoroethane (HFA 134a))

Ethanol anhydrous

Purified water

Citric acid anhydrous.

Not applicable.

2 years.

Protect from direct sunlight, heat and frost.

If the Inhaler has been exposed to low temperatures, the patient should take the metal canister out of the plastic case and warm it in their hands for a minimum of two minutes.

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

The inner packaging is a 19 ml silver anodised aluminium container fitted with a suitable 50 microliter metering valve and the plastic actuator. The valve contains a thermoplastic 2-part core, cup (body), metering chamber, 2 elastomeric seats and gasket, a metallic ferrule and a spring. The plastic actuator body & cap are made up of polypropylene.

Each container is filled to deliver 200 metered doses.

Pack sizes

For DE, SE, BG, CZ, BE, EL, HR, HU, NO, PL, PT, SI and SK.

Single pack

Each single pack contain a canister with 200 actuations.

For DE and PL

Multipack

400 actuations (2 x 200). Bundle pack of 2 single packs.

600 actuations (3 x 200). Bundle pack of 3 single packs.

For DE

Hospital pack

2000 actuations (10 x 200). Bundle pack of 10 single packs. Component of a hospital pack, can’t be sold separately.

Not all pack sizes may be marketed.

For detailed instructions on use of the medicinal product please refer to Patient Information Leaflet.

Cleaning

It is important to clean your inhaler regularly. Otherwise it may not work properly.

Once the white mouthpiece is dry, replace the canister and the cap

DO NOT PUT THE METAL CANISTER INTO WATER

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

ELC GROUP s.r.o.

Karolinská 650/1,Karlín 186 00,Prague Czech Republic.

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2015-10-01