Consumer medicine information

Atrovent Metered Dose Inhaler

Ipratropium bromide monohydrate

BRAND INFORMATION

Brand name

Atrovent Metered Aerosol (CFC-free)

Active ingredient

Ipratropium bromide monohydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Atrovent Metered Dose Inhaler.

What is in this leaflet

This leaflet answers some common questions about Atrovent Metered Aerosol.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Atrovent Metered Aerosol against the benefits it is expected to have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

This leaflet was last updated on the date at the end of this leaflet. More recent information may be available. The latest Consumer Medicine Information is available from your pharmacist, doctor or from www.medicines.org.au and may contain important information about the medicine and its use of which you should be aware.

Keep this leaflet with the medicine. You may need to read it again.

What Atrovent Metered Aerosol is used for

Atrovent Metered Aerosol is inhaled into the lungs for the maintenance treatment of difficulty in breathing, wheezing or coughing in:

  • asthma
  • chronic obstructive pulmonary disease, also called COPD.

Asthma is a disease where the lining of the lungs becomes inflamed (red and swollen), making it difficult to breathe. This may be due to an allergy to house dust mites, smoke or other irritants.

COPD is a serious lung condition that can cause difficulty in breathing and constant coughing. The term COPD is associated with the conditions chronic bronchitis and emphysema. Symptoms of COPD include shortness of breath, cough, chest discomfort and coughing up phlegm.

Atrovent Metered Aerosol contains the active ingredient ipratropium bromide monohydrate. It belongs to a group of medicines called anticholinergic bronchodilators.

Atrovent Metered Aerosol opens up the air passages in people suffering from asthma and chronic obstructive pulmonary disease (COPD).

It begins to act quickly after use but may take up to 2 hours to give maximum benefit.

Ask your doctor if you have any questions about why Atrovent Metered Aerosol has been prescribed for you. Your doctor may have prescribed Atrovent Metered Aerosol for another reason.

There is no evidence that Atrovent Metered Aerosol is addictive.

Atrovent Metered Aerosol is available only with a doctor's prescription.

Before you use Atrovent Metered Aerosol

When you must not use it

Do not use Atrovent Metered Aerosol if you have an allergy to:

  • ipratropium bromide
  • similar medicines which contain atropine or medicines like atropine
  • any of the ingredients listed at the end of this leaflet
  • any other anticholinergic medicines.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not use Atrovent Metered Aerosol after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start using Atrovent Metered Aerosol, contact your doctor or pharmacist.

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor or pharmacist if you are pregnant, intend to become pregnant, are breastfeeding or plan to breastfeed. Your doctor or pharmacist will discuss the possible risks and benefits of using Atrovent Metered Aerosol during pregnancy and breastfeeding.

Tell your doctor if you have or have had any of the following medical conditions:

  • glaucoma (high pressure in the eye)
  • difficulty or pain when passing urine
  • constipation
  • cystic fibrosis.

If you have not told your doctor or pharmacist about any of the above, tell them before you start using Atrovent Metered Aerosol.

Using other medicines

Tell your doctor or pharmacist if you are using any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Atrovent Metered Aerosol may interfere with each other. These include:

  • medicines used to treat heart problems such as adrenaline
  • medicines used to treat asthma or COPD such as theophylline, salbutamol and tiotropium.

These medicines may be affected by Atrovent Metered Aerosol, or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using Atrovent Metered Aerosol.

How to use Atrovent Metered Aerosol

Each puff must be properly inhaled through the mouth for Atrovent Metered Aerosol to work. At the end of this leaflet you will find instructions on how to use Atrovent Metered Aerosol correctly.

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you are not sure how to use the inhaler, ask your doctor or pharmacist for help.

Children should only use their inhaler on medical advice and with the help of an adult.

If you find it difficult to breathe in and use your inhaler at the same time, talk to your doctor or pharmacist. They may be able to recommend another method.

How much to use

The usual doses for adults and children are stated below.

Adults:
2 to 4 puffs, three to four times daily (at regular intervals), up to a maximum of 16 puffs a day.

Children 6 to 12 years:
1 to 2 puffs, three to four times daily (at regular intervals), up to a maximum of 8 puffs a day.

Children under 6 years:
1 puff, three times daily (at regular intervals).

Depending on your condition and specific needs, your doctor may advise you to take a different dose.

When to use it

Use your medicine at about the same time each day. Using it at the same time each day will have the best effect. It will also help you remember when to use it.

If you forget to use it

If it is almost time for your next dose, skip the dose you missed and have your next dose when you are meant to.

Otherwise, use it as soon as you remember, and then go back to using your medicine as you would normally.

Do not use a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to use your medicine, ask your pharmacist for some hints.

How long to use it

Continue using Atrovent Metered Aerosol for as long as your doctor tells you. Atrovent Metered Aerosol helps control your condition, but does not cure it. It is important to keep using it even if you feel well.

If you use too much (overdose)

Immediately telephone your doctor or pharmacist or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Emergency at the nearest hospital, if you think that you or anyone else may have used too much Atrovent Metered Aerosol. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include:

  • a fast or irregular heart beat
  • dry mouth
  • blurred vision.

While you are using Atrovent Metered Aerosol

Things you must do

Stop using Atrovent Metered Aerosol and tell your doctor immediately if you get sudden tightness of the chest, coughing, wheezing or breathlessness immediately after using Atrovent Metered Aerosol. These may be signs of a condition called bronchospasm.

If you have an Asthma or COPD Action Plan that you have agreed with your doctor, follow it closely at all times.

If you find that the usual dose of Atrovent Metered Aerosol is not giving as much relief as before, or you need to use it more often, contact your doctor so that your condition can be checked. This is important to ensure your breathing problem is controlled properly.

Continue using Atrovent Metered Aerosol for as long as your doctor or pharmacist tells you.

Keep all your doctor's appointments so that your progress can be checked.

Make sure you keep Atrovent Metered Aerosol with you at all times.

Contact your doctor immediately if you experience irritation or a feeling of having something in the eye, or any disturbances with your sight (blurred vision, visual halos or coloured images) together with red eyes, during or after using Atrovent Metered Aerosol. This may mean that you have developed a serious eye condition called narrow-angle glaucoma. This can happen if the spray gets in your eyes.

Tell any other doctors, dentists, and pharmacists who are treating you that you are using Atrovent Metered Aerosol.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using Atrovent Metered Aerosol.

If you plan to have surgery, tell the surgeon or anaesthetist that you are using Atrovent Metered Aerosol. It may affect other medicines during surgery.

If you become pregnant while using Atrovent Metered Aerosol tell your doctor or pharmacist immediately.

Things you must not do

Do not take any other medicines for your breathing problems without checking with your doctor.

Do not give Atrovent Metered Aerosol to anyone else, even if they have the same condition as you.

Do not use Atrovent Metered Aerosol to treat any other complaints unless your doctor or pharmacist tells you to.

Do not stop using Atrovent Metered Aerosol, or lower the dosage, without checking with your doctor or pharmacist.

Do not allow the Atrovent Metered Aerosol spray to enter the eyes.

Things to be careful of

Be careful driving or operating machinery until you know how Atrovent Metered Aerosol affects you.

Atrovent Metered Aerosol may cause dizziness and blurred vision in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous. Children should be careful when performing physical activities.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Atrovent Metered Aerosol.

This medicine helps most people with asthma or COPD, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the following list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

If you get any side effects, do not stop using the Atrovent Metered Aerosol without first talking to your doctor or pharmacist.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • headache
  • dizziness
  • dry or sore mouth
  • throat irritation
  • cough
  • nausea, vomiting
  • a change in bowel movements (e.g. constipation, diarrhoea)
  • wind, indigestion, reflux (an unusual backflow of fluid).

These are the more common side effects of Atrovent Metered Aerosol. Usually they are mild and short-lived.

Tell your doctor as soon as possible if you experience difficulty passing urine. This is a serious side effect that may require medical attention.

If any of the following happen, tell your doctor immediately or go to Emergency at your nearest hospital:

  • difficulty breathing or worsening of your breathing problems
  • spasm of the muscles around the voice box, causing choking
  • swelling of the throat
  • fast or irregular heart beat, also called palpitations
  • pounding heart beat
  • allergic reaction (shortness of breath, wheezing or troubled breathing; swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin)
  • irritation or a feeling of having something in the eye, dilated pupils, blurred vision, visual halos or coloured images.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell. Other side effects not listed above may occur in some people.

After using Atrovent Metered Aerosol

Cleaning

Clean and dry your mouthpiece at least once a week. It is important to keep the mouthpiece of your inhaler clean and dry. It may not work as well if it gets dirty. Follow the instructions at the end of this leaflet for cleaning your mouthpiece.

Storage

Keep your inhaler in a cool dry place where the temperature stays below 25°C.

Do not store Atrovent Metered Aerosol or any other medicine in the bathroom or near a sink.

Do not leave it in the car on hot days or on window sills. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor or pharmacist tells you to stop using Atrovent Metered Aerosol or it has passed its expiry date, ask your pharmacist what to do with any that are left over.

Do not puncture the container or throw it into a fire.

Product description

What it looks like

Atrovent Metered Aerosol is supplied in a can containing 200 puffs.

Ingredients

Each Atrovent Metered Aerosol dose contains 21 micrograms ipratropium bromide monohydrate as the active ingredient.

It also contains:

  • citric acid
  • purified water
  • absolute ethanol
  • norflurane.

Atrovent Metered Aerosol does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Atrovent Metered Aerosol is supplied in Australia by:

Boehringer Ingelheim Pty Limited
ABN 52 000 452 308
Sydney NSW
www.boehringer-ingelheim.com.au

This Consumer Medicine Information was revised October 2019.

® Atrovent is a registered trade mark of Boehringer Ingelheim

© Boehringer Ingelheim Pty Limited 2019

Australian Registration Number:

AUST R 91129

Atrovent®

Metered Aerosol
ipratropium bromide monohydrate

Directions for use

The mouthpiece has been designed for use with the Atrovent Metered Aerosol canister so that you always get the right amount of medicine.

The mouthpiece must never be used with any other metered aerosol canister. The Atrovent Metered Aerosol canister must not be used with any mouthpiece other than the one supplied with this product.

The container is under pressure and should not be opened by force or exposed to temperatures above 50°C.

How to use the metered aerosol

Note:

Before first use of a new inhaler, prime it by activating twice into the atmosphere.

Before use if the inhaler has not been used for 3 days, reprime by activating once into the atmosphere.

  1. Remove the protective cap from the short end of the mouthpiece.
  2. Hold the inhaler with the arrow on the canister pointing upwards. Do not spray into or around the eyes.
  3. Breathe out fully, to the end of a normal breath.
  4. Place the open end of the mouthpiece between the lips but not past the teeth (Figure 1).

  1. Breathe in slowly through the mouth and at the same time firmly press the canister down once. Do not stop breathing when you press on the canister - continue to take a full, deep breath.
  2. Hold your breath for about ten seconds if possible, then breathe out slowly. Remove the inhaler from your mouth.
  3. If a second or subsequent inhalation is necessary, start again from instruction 3.

Replace the protective cap on the mouthpiece.

How to check how full your inhaler is

Your inhaler is not transparent and makes almost no sound when it is shaken, so it is difficult to know when your inhaler is nearly empty.

The inhaler will deliver 200 puffs. When the labelled number of doses have been used (usually after 3 weeks when used as recommended) the canister may still appear to contain a small amount of fluid. The inhaler should, however, be replaced so that you can be certain that you are getting the right amount of medicine in each actuation.

Care and cleaning

In order to obtain the best service from your Atrovent Metered Aerosol, these simple directions on maintenance should be carefully observed.

One of the most common causes of failure of the metering device of the inhaler to function is a dirty or blocked mouthpiece.

Always replace the protective cap on the mouthpiece after use to prevent the inside of the mouthpiece and canister from becoming dusty.

Clean your mouthpiece at least once a week. It is important to keep the mouthpiece of your inhaler clean to ensure that medicine does not build up and block the spray.

Remember to take out the canister before you wash the mouthpiece. When removing the canister from the mouthpiece pull out carefully to avoid bending the thin plastic stem.

Never press the thin plastic stem of the canister against a firm surface to check for function. This may bend the stem and lead to malfunction of the inhaler.

For cleaning, first take off the dust cap and remove the canister from the mouthpiece. Rinse warm water through the mouthpiece until no medication build-up and/or dirt is visible (Figure 2).

After cleaning, shake out the mouthpiece and let it air-dry without using any heating system (Figure 3). Once the mouthpiece is dry, replace the canister and the dust cap.

Using Atrovent Metered Aerosol with a spacer

Your doctor or pharmacist may suggest that you use a device called a 'spacer' with your inhaler, to help you use your inhaler more effectively.

A spacer is a holding chamber into which you spray your inhaler before inhaling.

Follow the instructions supplied with the spacer, to use your inhaler and spacer together properly.

Before first using your spacer, wash it with warm water and a small amount of detergent. Allow it to dry without rinsing, or drying with a cloth. Repeat this cleaning process at least once every month. This will help keep your spacer clean and to work properly.

Make sure you breathe in and out through the spacer after each puff from your inhaler. If you need to be shown how to use your spacer, or if you are having difficulties using your spacer, discuss this with your pharmacist.

Published by MIMS October 2022

BRAND INFORMATION

Brand name

Atrovent Metered Aerosol (CFC-free)

Active ingredient

Ipratropium bromide monohydrate

Schedule

S4

 

1 Name of Medicine

Ipratropium bromide monohydrate.

2 Qualitative and Quantitative Composition

Atrovent contains ipratropium bromide monohydrate 21 micrograms [equivalent to 20 micrograms of ipratropium bromide] per actuation.

Excipients with known effect.

Contains 8.415 mg ethanol absolute per actuation.
For full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Atrovent is a pressurised inhalation solution.
Each Atrovent metered dose aerosol can is filled with a clear, colourless liquid, free from suspended particles.

4 Clinical Particulars

4.1 Therapeutic Indications

Atrovent metered aerosol is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with asthma and chronic obstructive pulmonary disease (COPD).

4.2 Dose and Method of Administration

Note.

One puff (metered dose) of Atrovent contains 21 micrograms of ipratropium bromide monohydrate [equivalent to 20 micrograms of ipratropium bromide].
If the response to the treatment is inadequate, medical advice should be sought so that appropriate measures can be taken. It is advisable not to greatly exceed the recommended daily dose as this suggests additional therapeutic modalities may be needed.
If therapy does not produce a significant improvement or if the patient's condition gets worse, medical advice must be sought in order to determine a new plan of treatment. In the case of acute or rapidly worsening dyspnoea, a doctor should be consulted immediately.

Adults.

Two puffs 3 to 4 times daily, although some patients may need up to 4 puffs at a time to obtain maximum benefit during early treatment.

Children.

Administration to children should be supervised by an adult.

6-12 years.

One or two puffs 3 to 4 times daily.

Under 6 years.

One puff 3 times daily.
Patients with poor inhaler technique will benefit from the consistent use of a spacer device with their metered aerosol. Use of a spacer will also decrease the amount of drug deposited in the mouth and back of the throat, and therefore reduce the incidence of local irritation in susceptible patients.
In those people using a spacer, a change in formulation of the drug used, or a change in the make of the spacer may be associated with alterations in the amount of drug delivered to the lungs. The clinical significance of these alterations is uncertain. However, in these situations, the person should be monitored for any change in their condition.
If using a spacer, the patient should be instructed to breathe in and out after each actuation of the drug into the spacer. Any delay should be kept to a minimum.
Static on the walls of the spacer may cause variability in drug delivery. Patients should be instructed to wash the spacer in warm water and detergent and allow it to dry without rinsing or drying with a cloth. This should be performed before initial use of the spacer and at least monthly thereafter.
The Atrovent metered aerosol can must only be used with the mouthpiece supplied with the product.

4.3 Contraindications

Known hypersensitivity to atropine or its derivatives (such as the active substance ipratropium bromide) or to any of the other ingredients of Atrovent.

4.4 Special Warnings and Precautions for Use

Hypersensitivity.

Immediate hypersensitivity reactions may occur after administration of Atrovent, as demonstrated by rare cases of urticaria, angio-oedema, 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.

Anticholinergic effects.

Like other drugs with anticholinergic activity, ipratropium bromide should be avoided or used with caution in patients where atropine-like effects may precipitate or exacerbate a pre-existing clinical condition. Patients at particular risk are those with eyes with narrow iridocorneal angles as acute angle-closure glaucoma may be precipitated, or patients with a tendency towards urinary retention or constipation.

Ocular complications.

Atrovent should be used with caution in patients predisposed to narrow-angle glaucoma.
There have been isolated reports of ocular complications (mydriasis, increased intraocular pressure, acute angle glaucoma, eye pain) as a result of direct eye contact of ipratropium bromide formulations. Thus, patients must be instructed in the correct administration of Atrovent and warned not to allow the aerosol to enter the eyes.
Patients who may be predisposed to glaucoma should be specifically warned to protect their 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 angle-closure glaucoma. Should any combination of these symptoms develop, treatment with miotic drops should be initiated and specialist advice sought immediately.

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-neck obstruction).

Gastro-intestinal motility disturbances.

Patients with cystic fibrosis may be more prone to gastrointestinal motility disturbances.

Propellants.

Atrovent CFC-free metered aerosol contains the hydrofluoroalkane propellant norflurane. In animal studies, norflurane has been shown to have no significant pharmacological effects, except at very high exposure concentrations when narcosis and a relatively weak sensitisation to the arrhythmogenic effects of catecholamines were found. The potency of the cardiac sensation was less than that of trichloromethane.
Excessive inhalation of the aerosol should, however, be avoided as this carries a potential hazard, both from the propellant as well as from overdosage of the active therapeutic agent contained in the formulation. The recommended dose should not be exceeded and the patients should be so informed.

Alcohol content.

Atrovent contains about 8 mg of alcohol (ethanol) in each actuation. The amount in each actuation of this medicine is equivalent to less than 1 mL beer or 1 mL wine. The small amount of alcohol in this medicine will not have any noticeable effects.

Use in the elderly.

No data available.

Paediatric use.

Paediatric patients can use Atrovent metered aerosol at the recommended dose.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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.
Beta-adrenergics and xanthine preparations may intensify the bronchodilatory effect of Atrovent.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Clinical data on fertility are not available for ipratropium bromide.
(Category B1)
Care is recommended during pregnancy, particularly in the first trimester. The safety of Atrovent during pregnancy has not been established. The benefits of using Atrovent when pregnancy is confirmed or suspected must be weighed against possible hazards to the foetus. Studies in rats, mice and rabbits showed no embryo-toxic nor teratogenic effects.
No specific studies are available to determine the excretion of ipratropium bromide in human breast milk. Although lipid-insoluble quaternary cations pass into breast milk, it is unlikely that ipratropium bromide would reach the infant to an important extent, especially when administered by inhalation. However, as many drugs are excreted into breast milk, caution should be exercised when Atrovent is administered to breastfeeding mothers.

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. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.
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. The most frequent side effects reported in clinical trials were headache, dizziness, throat irritation, cough, gastrointestinal disorders (including constipation, diarrhoea, gastrointestinal motility disorder, dry mouth, nausea, stomatitis, oedema mouth and vomiting).
If the substance enters the eyes by inappropriate handling, mild and reversible disturbance of accommodation may occur. Other ocular complications have also been reported (see Section 4.4 Special Warnings and Precautions for Use). However, acute angle-closure glaucoma has been reported following direct eye contact.
Allergic-type reactions such as angio-oedema of the tongue, lips and face may also occur.
The following adverse reactions have been reported during use of Atrovent in clinical trials and during the post-marketing experience at the following frequency: 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). See Table 1.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
No symptoms specific to over-dosage have been encountered. In view of the wide therapeutic range and topical administration of Atrovent inhalation solutions, no serious anticholinergic symptoms are to be expected. Minor systemic manifestations of anticholinergic action, including dry mouth, visual accommodation disorder and tachycardia may occur.

5 Pharmacological Properties

Pharmacotherapeutic group: Anticholinergics. ATC Code: R03BB01.

5.1 Pharmacodynamic Properties

Mechanism of action.

Atrovent is an anticholinergic bronchodilator. It appears to inhibit vagally mediated reflexes by antagonising the action of acetylcholine, the transmitter agent released from the vagal nerve. Anticholinergics prevent the increase in intracellular calcium concentration caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle. Bronchodilation following inhalation of Atrovent is a local, site specific effect at the bronchial smooth muscle. Atrovent has no deleterious effect on airway mucous secretion or mucociliary clearance.
The time course of action of Atrovent also differs from the β2-agonists in that although the onset of bronchodilator response is seen within 3-5 minutes of administration, peak response is not reached until 1.5-2 hours after inhalation. The duration of significant bronchodilator action is up to 6 hours.
Atrovent may be used in combination with β2-agonists. There is evidence that in patients who respond to Atrovent, the concurrent administration of Atrovent and β2-agonists produces a greater relief of bronchospasm than either drug given alone.

Clinical trials.

The use of Atrovent metered aerosol, delivered using CFC-containing propellants, is well established in clinical practice. A clinical programme has been conducted to demonstrate the therapeutic equivalence of Atrovent CFC-free and CFC-containing metered aerosols. The safety and efficacy of Atrovent CFC-free metered aerosol, in chronic obstructive pulmonary disease (COPD) and asthma, was established from the results of one 12-month and two 12-week safety and efficacy trials conducted in COPD, a 12-week study in asthmatic adults and a 12-week safety study in asthmatic children.
A randomised, open-label, parallel design 12-month study in COPD patients, compared the safety and efficacy of Atrovent metered aerosols containing either CFCs (n =151) or norflurane (n = 305). Time profiles of forced expiratory volume in one second (FEV1) mean changes from baseline on all test days demonstrated the efficacy and overall comparability of the Atrovent CFC-free and CFC-containing aerosols. The two formulations were generally comparable throughout the trial with respect FEV1 area under the curve for 0 to 6 hours (AUC0-6). The overall safety profile indicated that both treatments were well tolerated.
A 12-week, double-blind, randomised trial in COPD patients, comparing safety and efficacy of Atrovent CFC-free and CFC-containing metered aerosols (n = 118 and 56 respectively), concluded there were no differences in respect of changes in morning and evening peak expiratory flow rates. In addition, a randomised, double-blind, placebo and active controlled study of 12-weeks duration in COPD patients, concluded that Atrovent CFC-free 42 microgram (n = 125) and 84 microgram (n = 127) were significantly more effective than placebo in terms of adjusted mean FEV1 AUC0-6 and peak response. For each trial, the safety profiles of both formulations were found to be comparable.
A multi-dose comparison of Atrovent CFC-free with CFC-containing metered aerosol in a 12-week, double-blind, parallel group study of adult patients with bronchial asthma, demonstrated that patients who switched to the CFC-free aerosol (n = 159) from the CFC-containing aerosol (n = 75), had no change in daily peak expiratory flow rate values and usage of rescue medication. Similar results were observed in paediatric patients with bronchial asthma in a 12-week, double-blind, parallel group study comparing Atrovent CFC-free (n = 133) with the Atrovent CFC-containing aerosol (n = 58). For both studies, the adverse event profile of both formulations was very similar for all events reported.
In summary the data shows that Atrovent CFC-free metered aerosol is comparable in terms of efficacy and safety to the CFC-containing formulation.

5.2 Pharmacokinetic Properties

Absorption.

Following inhalation, 10 to 30% of the dose (depending on the formulation and inhalation technique) is generally deposited in the lungs. The major part of the dose is swallowed and passes into the gastrointestinal tract. Due to the low gastrointestinal absorption of ipratropium bromide, the bioavailability of the portion of the dose swallowed accounts for approximately 2% of the dose. 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) and has nearly complete systemic availability.
From renal excretion data (0-24 hours), the total systemic bioavailability (pulmonary and gastrointestinal portions) of inhaled doses of ipratropium bromide was estimated to be in the range 7 to 28%. This is also a valid range for inhalation from Atrovent CFC-free because the kinetic results (renal excretion, AUC and Cmax) from the CFC-free and the CFC containing formulations are approximately comparable.

Distribution.

Kinetic parameters describing the disposition of ipratropium bromide were calculated from plasma concentrations after intravenous administration. A rapid biphasic decline in plasma concentrations is observed. The volume of distribution (Vz) is 338 L (approximately 4.6 L/kg). The half-life of the terminal elimination phase is about 1.6 hours. The drug is less than 20% bound to plasma proteins. The ipratropium ion does not cross the blood brain barrier, consistent with the ammonium structure of the molecule. The main urinary metabolites bind poorly to the muscarinic receptor and have no activity.

Metabolism.

The mean total clearance of the drug is 2.3 L/min. The major portion, approximately 60% of the systemically available dose, is eliminated by metabolic degradation, probably in the liver.

Excretion.

Approximately 40% of the systemically available dose is cleared via urinary excretion, corresponding to an experimental renal clearance of 0.9 L/min. After oral dosing less than 1% of the dose is renally excreted, indicating an insignificant absorption of ipratropium bromide from the gastrointestinal tract.
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), are excreted via the biliary faecal route. The dominant excretion of drug related radioactivity occurs via the kidneys.

5.3 Preclinical Safety Data

Genotoxicity.

Results of various mutagenicity studies (Ames test, mouse dominant lethal test, mouse micronucleus test and chromosome aberration of bone marrow in Chinese hamsters) were negative.

Carcinogenicity.

Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic potential at dietary doses up to 6 mg/kg/day for Atrovent.

6 Pharmaceutical Particulars

6.1 List of Excipients

In addition to ipratropium bromide, Atrovent metered aerosol contains citric acid, purified water, ethanol absolute and the non-chlorofluorocarbon (CFC-free) propellant norflurane (also known as HFA [hydrofluoroalkane] 134a).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.
Avoid storage in direct sunlight or heat. Do not puncture or incinerate, as canister may explode.

6.5 Nature and Contents of Container

Atrovent is contained in a 17 mL stainless steel metered dose aerosol can complete with mouthpiece, containing 200 metered doses.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Ipratropium bromide is a synthetic quaternary ammonium compound, chemically related to atropine. The addition of an N-isopropyl group distinguishes the molecule from atropine and is responsible for a lower lipid solubility.
Ipratropium bromide is a white or off-white crystalline substance. It is freely soluble in methanol, soluble in water and sparingly soluble in ethanol 96% (v/v).
The chemical name for ipratropium bromide (as monohydrate) is (1R,3r,5S,8r)-3-[(RS)-(3-hydroxy-2-phenyl-propanoyl)-oxy]-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1]octane bromide monohydrate.
The molecular formula is C20H30NO3Br.H2O and the molecular weight is 430.4.
Ipratropium bromide has the following structural formula:

CAS number.

66985-17-9.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes