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.

SUMMARY CMI

Atrovent® Metered Dose Inhaler

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Atrovent MDI?

Atrovent metered dose inhaler (Atrovent MDI) contains the active ingredient ipratropium bromide monohydrate. Atrovent MDI is used to make breathing easier for people with asthma or chronic obstructive pulmonary disease (COPD).

For more information, see Section 1. Why am I using Atrovent MDI? in the full CMI.

2. What should I know before I use Atrovent MDI?

Do not use if you have ever had an allergic reaction to ipratropium, atropine or any medicines like atropine or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Atrovent MDI? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Atrovent MDI and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Atrovent MDI?

Inhale each puff through the mouth. The usual doses are:

  • 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)

More instructions can be found in Section 4. How do I use Atrovent MDI? in the full CMI.

5. What should I know while using Atrovent MDI?

Things you should do
  • Stop using Atrovent MDI and tell your doctor immediately if you get sudden chest tightness, coughing, wheezing or breathlessness immediately after using Atrovent MDI.
  • Tell your doctor immediately if you experience irritation of the eye or any disturbances with your sight together with red eyes.
  • Remind any doctor, dentist or pharmacist you visit that you are using Atrovent MDI.
Things you should not do
  • Do not stop using Atrovent MDI, or lower the dosage, without checking with your doctor or pharmacist.
  • Do not allow the spray from Atrovent MDI to enter the eyes.
Driving or using machines
  • Be careful driving or operating machinery until you know how Atrovent MDI affects you.
  • Atrovent MDI may cause dizziness and blurred vision in some people.
Looking after your medicine
  • Clean and dry your mouthpiece at least once a week.
  • Keep your inhaler in a cool dry place (below 25°C) and keep out of reach of children.
  • Do not puncture the container or throw it into a fire.

For more information, see Section 5. What should I know while using Atrovent MDI? in the full CMI.

6. Are there any side effects?

Common but usually mild potential side effects include headache, dizziness, throat irritation, cough, dry mouth, nausea and digestion-related issues (e.g. constipation, diarrhoea, indigestion, reflux and wind).

Serious potential side effects that require medical attention include allergic reaction, difficulty in breathing, heart beat changes, eye irritation or vision changes and difficulty in passing urine.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Atrovent® Metered Dose Inhaler

Active ingredient: ipratropium bromide monohydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Atrovent MDI. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Atrovent MDI.

Where to find information in this leaflet:

1. Why am I using Atrovent MDI?
2. What should I know before I use Atrovent MDI?
3. What if I am taking other medicines?
4. How do I use Atrovent MDI?
5. What should I know while using Atrovent MDI?
6. Are there any side effects?
7. Product details

1. Why am I using Atrovent MDI?

Atrovent metered dose inhaler (Atrovent MDI) contains the active ingredient ipratropium bromide monohydrate. Atrovent MDI is a type of bronchodilator, which are medicines that help to open up the airways.

Atrovent MDI is used to make breathing easier for people with asthma or chronic obstructive pulmonary disease (COPD).

Asthma is a disease where the lining of the lungs become inflamed (red and swollen), making it difficult to breathe.

COPD (which includes chronic bronchitis and emphysema) is a long-term, serious lung condition. You may have difficulty breathing (shortness of breath or wheezing), cough, tightness in your chest or coughing up phlegm.

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

2. What should I know before I use Atrovent MDI?

Warnings

Do not use Atrovent MDI if:

  • You are allergic to ipratropium, or any of the ingredients listed at the end of this leaflet.
  • You are allergic to atropine or medicines like atropine.

Check with 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 (a serious condition that affects the lungs and digestive system)

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor if you are pregnant, intend to become pregnant, are breastfeeding or intend to breastfeed.

Your doctor can discuss with you the risks and benefits involved.

Alcohol content

Atrovent MDI contains about 8 mg of alcohol in each puff. The amount in each puff is equal to less than 1 ml beer or 1 ml wine. The small amount of alcohol in Atrovent MDI will not have any noticeable effects.

3. What if I am taking other medicines?

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

Some medicines may be affected by Atrovent MDI or may interfere with how Atrovent MDI works. These include:

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

You may need different amounts of your medicines, or you may need to take different medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Atrovent MDI.

4. How do I use Atrovent MDI?

How much to use

The recommended doses are:

  • 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).

Your doctor may advise you to use a different dose, depending on your condition and specific needs.

Follow the instructions provided by your doctor or pharmacist and use Atrovent MDI until your doctor tells you to stop.

When to use Atrovent MDI

Use Atrovent MDI at about the same time each day.

How to use Atrovent MDI

Detailed instructions (with diagrams) on how to use Atrovent MDI is available online:
medsinfo.com.au/media/byiatrcf
This Instructions for Use leaflet is also enclosed in your carton.

  • Inhale each puff properly through the mouth.
  • Ask your doctor or pharmacist for help if:
    - you are not sure how to use the inhaler
    - you find it difficult to breathe in and use your inhaler at the same time. Your doctor or pharmacist may recommend another method, such as using a spacer with the inhaler.
  • Children should only use their inhaler on medical advice and with the help of an adult.

If you forget to use Atrovent MDI

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 take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

Ask your doctor or pharmacist if you are not sure what to do.

If you use too much Atrovent MDI

If you think that you have used too much Atrovent MDI, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Symptoms of an overdose may include:

  • a fast or irregular heartbeat
  • dry mouth
  • blurred vision.

5. What should I know while using Atrovent MDI?

Things you should do

  • Stop using Atrovent MDI and contact your doctor immediately if you get sudden tightness of the chest, coughing, wheezing or breathlessness immediately after using Atrovent MDI. These may be signs of a condition called bronchospasm.
  • 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 MDI. 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 your doctor immediately if you become pregnant
  • 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 MDI 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.
  • Remind any doctor, dentist or pharmacist you visit that you are using Atrovent MDI.
  • If you plan to have surgery, tell the surgeon or anaesthetist that you are using Atrovent MDI. It may affect other medicines used during surgery.
  • Keep all of your doctor's appointments so that your progress can be checked.
  • Keep your Atrovent MDI with you at all times.

Things you should not do

  • Do not take any other medicines for your breathing problems without checking with your doctor.
  • Do not give Atrovent MDI to anyone else, even if they have the same condition as you.
  • Do not use Atrovent MDI to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not stop using Atrovent MDI or lower the dosage without checking with your doctor or pharmacist.
  • Do not allow the Atrovent MDI spray to enter your eyes.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Atrovent MDI affects you.

Atrovent MDI 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.

Looking after your medicine

  • Clean and dry your mouthpiece at least once a week. Follow the cleaning directions in the Instructions for Use leaflet (the leaflet is enclosed in the carton and is also available online via the link in Section 4. How do I use Atrovent MDI?). It is important to keep the mouthpiece of your inhaler clean and dry. It may not work as well if it gets dirty.
  • Keep your inhaler in a cool dry place where the temperature stays below 25°C.
  • Do not store it:
    - in the bathroom or near a sink, or
    - in the car or on window sills.
  • Keep Atrovent MDI where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

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

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

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

Less serious side effects

Less serious side effectsWhat to do
Brain and nerves:
  • headache
  • dizziness
Mouth, throat and airways:
  • dry mouth
  • sore or swollen mouth
  • throat irritation
  • cough
Gut and digestion:
  • nausea or vomiting
  • change in bowel movements (e.g. constipation, diarrhoea)
  • wind
  • indigestion
  • reflux (an unusual backflow of fluid)
Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Signs of an allergic reaction:
  • 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.
Mouth, throat and airways:
  • difficulty breathing or worsening of your breathing problems
  • spasm of the muscles around the voice box, causing choking
  • swelling of the throat
Heart:
  • fast or irregular heartbeat
  • pounding heartbeat
Eyes:
  • irritation or a feeling of having something in the eye
  • dilated pupils
  • blurred vision
  • visual halos or coloured images
Bladder:
  • difficulty passing urine
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Atrovent MDI contains

Each dose (puff) of Atrovent MDI contains:

Active ingredient
(main ingredient)		ipratropium bromide monohydrate (21 micrograms)
Other ingredients
(inactive ingredients)		citric acid
purified water
absolute ethanol
norflurane
Potential allergensalcohol

Do not take this medicine if you are allergic to any of these ingredients.

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

What Atrovent MDI looks like

Atrovent MDI (AUST R 91129) is supplied in a can with a mouthpiece and it contains 200 puffs.

Who distributes Atrovent MDI

Atrovent MDI is distributed in Australia by:

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

This leaflet was prepared in August 2022.

® Atrovent is a registered trademark of Boehringer Ingelheim

© Boehringer Ingelheim Pty Limited 2022

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