Consumer medicine information

Spiriva Respimat (with dose indicator)

Tiotropium

BRAND INFORMATION

Brand name

Spiriva Respimat (with dose indicator)

Active ingredient

Tiotropium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Spiriva Respimat (with dose indicator).

SUMMARY CMI

Spiriva® Respimat®

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 Spiriva Respimat?

Spiriva Respimat contains the active ingredient tiotropium. Spiriva Respimat is used to make breathing easier for people with chronic obstructive pulmonary disease (COPD) and asthma. If used to treat asthma you MUST use Spiriva Respimat in addition to other medicines called inhaled corticosteroids.

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

2. What should I know before I use Spiriva Respimat?

Do not use if you have ever had an allergic reaction to tiotropium, atropine, medicines like atropine (e.g. ipratropium or oxitropium) or any of the ingredients listed at the end of this leaflet.

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

For more information, see Section 2. What should I know before I use Spiriva Respimat? In the full CMI.

3. What if I am taking or using other medicines?

Some medicines may interfere with Spiriva Respimat and affect how it works.

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

4. How do I use Spiriva Respimat?

  • Spiriva Respimat is for inhalation use only.
  • Read the Instructions for Use and follow the diagrams that show you how to use the Spiriva Respimat re-usable inhaler.
  • The recommended dose is TWO PUFFS, once a day at the same time of the day. You need to take two puffs to get the full dose.

More instructions can be found in Section 4. How do I use Spiriva Respimat? In the full CMI.

5. What should I know while using Spiriva Respimat?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Spiriva Respimat.
  • Tell your doctor immediately if your breathing becomes more difficult while you are taking Spiriva Respimat.
Things you should not do
  • Do not use Spiriva Respimat to relieve an acute attack of breathlessness or wheezing.
  • Do not take Spiriva Respimat more frequently than once daily.
Driving or using machines
  • Spiriva Respimat may cause dizziness or blurred vision in some people.
  • Be careful before you drive or use any machines or tools until you know how Spiriva Respimat affects you.
Looking after your medicine
  • Keep Spiriva Respimat in a cool dry place where the temperature stays below 25°C. Do not freeze.
  • Exchange cartridge not later than three months after insertion.

For more information, see Section 5. What should I know while using Spiriva Respimat? In the full CMI.

6. Are there any side effects?

A common side effect in patients with COPD is dry mouth, which is usually mild.

Serious potential side effects that require medical attention include: worsening of breathing, difficulty swallowing, palpitations, vision changes, pain or difficulty passing urine, urinary tract infection and skin infection or ulcer. Patients who experience an allergic reaction or severe pain in the stomach with bloating, gut cramps and vomiting require urgent medical attention.

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

Spiriva® Respimat®

Active ingredient: tiotropium

Consumer Medicine Information (CMI)

This leaflet provides important information about using Spiriva Respimat. 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 Spiriva Respimat.

Where to find information in this leaflet:

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

1. Why am I using Spiriva Respimat?

Spiriva Respimat contains the active ingredient tiotropium (as bromide monohydrate). It belongs to a group of medicines called anticholinergics. Spiriva Respimat improves breathing by relaxing the breathing tubes or air passages that carry air to and from the lungs.

Spiriva Respimat is used to make breathing easier for people with:

  • chronic obstructive pulmonary disease (COPD)
  • asthma.

Chronic Obstructive Pulmonary Disease (COPD)

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. Spiriva Respimat helps to improve your COPD condition and prevent exacerbations (periodic worsening of symptoms) from occurring.

As COPD is a long-term condition, you should use Spiriva Respimat every day, even if you do not have breathing problems or other symptoms of COPD.

Asthma

Asthma is a serious lung condition 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, air pollution or other things that irritate your lungs.

The common symptoms of asthma include breathlessness, wheezing, a cough (sometimes brought on by exercise), and a feeling of tightness in the chest.

When used to treat asthma, you MUST use Spiriva Respimat every day in addition to other medicines called inhaled corticosteroids.

2. What should I know before I use Spiriva Respimat?

Warnings

Do not use Spiriva Respimat to treat an acute asthma attack or sudden attack of breathlessness, wheezing or coughing. You will need a different type of medicine known as a 'reliever' for this.

Tell your doctor immediately if you get sudden tightness of the chest, coughing, wheezing or breathlessness immediately after using Spiriva Respimat.

These may be signs of a condition called bronchospasm. Patients with asthma have an increased risk of developing this condition.

Do not use Spiriva Respimat if you are allergic to:

  • tiotropium (as bromide monohydrate), or any of the ingredients listed at the end of this leaflet.
  • atropine or substances related to it, e.g. ipratropium or oxitropium.

Check with your doctor if:

  • You have or have had any of the following medical conditions:
    - High pressure in the eye (glaucoma)
    - Kidney or liver problems
    - Problems with your prostate gland
    - Problems passing urine
    - You have suffered from a heart attack during the last 6 months or from any unstable or life threatening irregular heart beat or severe heart failure within the past year.

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 breast-feeding or intend to breastfeed.

Spiriva Respimat is not generally recommended for use in pregnant women.

Spiriva Respimat should not be used whilst breastfeeding unless the expected benefit outweighs any possible risk to the infant.

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

Children and adolescents

Do not give Spiriva Respimat to children below the age of 6 years. Spiriva Respimat is only for the treatment of asthma in children aged 6 years and older.

Children should use Spiriva Respimat with an adult's assistance.

Eyes

Do not allow the mist to enter your eyes. Should this occur, immediately flush your eyes with cold tap water for several minutes and immediately consult your doctor for further advice.

If the mist enters the eye, it may result in eye pain or discomfort, blurred vision, seeing halos around lights or coloured images in association with red eyes (i.e. narrow angle glaucoma). Eye symptoms may be accompanied by headache, nausea or vomiting.

Device

The Spiriva Respimat Re-usable inhaler can only be used with Spiriva Respimat cartridges.

3. What if I am taking or using other medicines?

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

Some medicines and Spiriva Respimat may interfere with each other. These include:

  • Other anticholinergic medicines such as glycopyrronium, aclidinium, umeclidinium or ipratropium.

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 Spiriva Respimat.

4. How do I use Spiriva Respimat?

If you have been prescribed Spiriva Respimat for your asthma it must be added on to your treatments that include an inhaled corticosteroid.

How much to use

Inhale TWO PUFFS, once a day at the same time of the day. You need to take two puffs to get the full dose.

Do not take more than the recommended dose.

Follow all the directions given to you by your doctor or pharmacist carefully.

When to use Spiriva Respimat

Use Spiriva Respimat at about the same time each day.

How to use Spiriva Respimat

  • Spiriva Respimat is for inhalation use only.
  • Make sure that you know how to use your Spiriva Respimat reusable inhaler properly.
  • Read the Instructions for Use and follow the diagrams that show you how to use the Spiriva Respimat re-usable inhaler.
  • The Instructions for Use are also available via the following hyperlink: medsinfo.com.au/media/byisprri
  • Use the Spiriva Respimat re-usable inhaler supplied in the pack to breathe in the solution containing the medicine from the Spiriva Respimat cartridge.
  • Insert the Spiriva Respimat cartridge into the Spiriva Respimat re-usable inhaler to prepare the inhaler for first use.
  • The Spiriva Respimat re-usable inhaler releases a mist of solution slowly and gently, making it easy to inhale it into your lungs where it is needed. The mist containing the medication is released by pressing the dose release button.
  • If you do not understand the instructions on how to use the Spiriva Respimat re-usable inhaler, ask your doctor or pharmacist for help.
  • Continue to use Spiriva Respimat for as long as your doctor tells you.

If you forget to use Spiriva Respimat

If you forget to use your Spiriva Respimat, use it as soon as you remember.

If it is almost time for your next dose, skip the dose you missed and inhale just one dose at your usual time the next day.

Do not take a double dose to make up for the dose 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 use too much Spiriva Respimat

If you think that you have used too much Spiriva Respimat, 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 fast or irregular heartbeat, blurred vision, nausea, stomach pain, dry mouth, constipation, difficulty passing urine.

5. What should I know while using Spiriva Respimat?

Things you should do

Tell your doctor immediately if:

  • You become pregnant while using Spiriva Respimat.
  • Your breathing becomes more difficult while you are using Spiriva Respimat.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Remind any doctor, dentist or pharmacist you visit that you are using Spiriva Respimat, especially if you are about to start any new medicine or if you are going to have surgery.

Pay attention to oral hygiene.

Dry mouth which has been observed in medicines like Spiriva Respimat may in the long term be associated with tooth decay.

If you are a smoker, you should stop smoking. Your doctor or pharmacist can advise you on the steps to take to quit smoking.

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

If you have been prescribed Spiriva Respimat for your asthma it must be added on to your treatments that include an inhaled corticosteroid. Continue taking the inhaled corticosteroid as prescribed by your doctor, even if you feel better.

Things you should not do

  • Do not use Spiriva Respimat to relieve an acute attack of breathlessness or wheezing. If you become wheezy or tight in the chest before your next dose of Spiriva Respimat is due, use a 'reliever puffer' in the usual way.
  • Do not use Spiriva Respimat to treat any other complaints unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not take any other medicines for your breathing problems without checking with your doctor.
  • Spiriva Respimat should only be used as the maintenance treatment of your COPD or asthma.
  • Do not stop using your medicine or lower the dosage without checking with your doctor. If you stop using it suddenly or lower the dosage, the signs and symptoms of your condition may worsen.
  • Do not take Spiriva Respimat more frequently than once daily.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Spiriva Respimat affects you.

This medicine may cause dizziness or 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.

Looking after your medicine

  • Refer to the Spiriva Respimat re-usable inhaler Instructions for Use on how to clean and take care of your Spiriva Respimat.
  • Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or tissue only, at least once a week. It is important to keep your inhaler clean and dry. It may not work as well if it gets dirty.
  • Exchange the cartridge not later than three months after insertion.
  • Do not use the Respimat re-usable inhaler for more than one year.
  • The recommended use is 6 cartridges per Spiriva Respimat re-usable inhaler.
  • Keep Spiriva Respimat in a cool dry place where the temperature stays below 25°C. Do not freeze.

Store it away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it 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 (located on the cartridge).

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 lists of side effects. You may not experience any of them.

Less serious side effects

Less serious side effectsWhat to do
Brain and nerves:
  • dizziness
  • trouble sleeping.
Nose and sinus:
  • nose bleeds
Mouth, throat and airways:
  • dry mouth (usually mild)
  • sore mouth, gums, or throat; swollen, red, sore tongue
  • sore, creamy-yellow, raised patches in the mouth or throat (oral thrush)
  • hoarse voice
  • cough
Gut and digestion:
  • heartburn
  • constipation.
Metabolism and Nutrition:
  • dehydration
Skin:
  • dry skin
  • rash.
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Eyes:
  • blurred vision
  • seeing halos around lights or coloured images in association with red eyes; high pressure in the eye (glaucoma)
Mouth, throat and airways:
  • difficulty swallowing
  • worsening of breathing problems (induced by the inhalation process). Inhaled medicines such as Spiriva Respimat may cause tightness of the chest, coughing, wheezing or breathlessness immediately after inhalation.
Heart:
  • feeling of fluttering, racing or skipping heart beats (palpitations).
Bladder:
  • difficulty or pain when passing urine.
  • signs of a urinary tract infection:
    - a frequent need to urinate
    - only passing a few drops of urine
    - burning pain or a 'scalding' sensation when urinating
    - feeling that the bladder is still full after urinating
    - pain above the pubic bone
    - blood in your urine.
Skin:
  • skin infection or skin ulcer
Speak to your doctor as soon as possible if you have any of these serious side effects.

Very serious side effects

Very serious side effectsWhat to do
Signs of an allergic reaction:
  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, mouth, tongue, or throat which may cause difficulty in swallowing or breathing
  • swelling of other parts of the body
  • rash, itching or hives on the skin.
Gut and digestion:
  • severe pain in the stomach with bloating, gut cramps and vomiting.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these very 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 prescription.

What Spiriva Respimat contains

Active ingredient
(main ingredient)		2.5 micrograms tiotropium (as bromide monohydrate) per puff.
Other ingredients
(inactive ingredients)
  • benzalkonium chloride
  • disodium edetate
  • purified water
  • hydrochloric acid.

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

What Spiriva Respimat looks like

Spiriva Respimat is composed of one cartridge with solution for inhalation and one Respimat re-usable inhaler. (AUST R 325662).

Single pack: 1 Spiriva Respimat re-usable inhaler and 1 Spiriva Respimat cartridge, providing 60 puffs (30 doses).

Triple pack: 1 Spiriva Respimat re-usable inhaler and 3 Spiriva Respimat cartridges, providing 60 puffs (30 doses) each. *

Single refill pack: 1 Spiriva Respimat cartridge, providing 60 puffs (30 doses).

Triple refill pack: 3 Spiriva Respimat cartridges, providing 60 puffs (30 doses) each. *

*Not all pack sizes may be marketed.

Who distributes Spiriva Respimat

Spiriva Respimat is distributed in Australia by:
Boehringer Ingelheim Pty Limited
ABN 52 000 452 308
Sydney, Australia
www.boehringer-ingelheim.com.au

This Consumer Medicine Information was prepared in February 2024.

®Spiriva and Respimat are registered trademarks of Boehringer Ingelheim

© Boehringer Ingelheim Pty Limited 2024

Published by MIMS May 2024

BRAND INFORMATION

Brand name

Spiriva Respimat (with dose indicator)

Active ingredient

Tiotropium

Schedule

S4

 

1 Name of Medicine

Tiotropium (as bromide monohydrate).

2 Qualitative and Quantitative Composition

Each puff contains tiotropium 2.5 micrograms, equivalent to tiotropium bromide monohydrate 3.1 micrograms.
Spiriva Respimat cartridges contain a clear, colourless, solution for inhalation filled into a plastic container which is inside an aluminium cylinder (cartridge) with a dose counter, for use with the Spiriva Respimat re-usable inhaler. The Spiriva Respimat re-usable inhaler has a green-coloured cap. The Spiriva Respimat cartridge is only intended for use with the Spiriva Respimat re-usable inhaler.

Excipients with known effect.

Spiriva Respimat contains 0.0011 mg benzalkonium chloride in each actuation.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

See Section 2 Qualitative and Quantitative Composition.

4 Clinical Particulars

4.1 Therapeutic Indications

COPD.

Spiriva Respimat is indicated for the long term maintenance treatment of bronchospasm and dyspnoea associated with chronic obstructive pulmonary disease (COPD). Spiriva Respimat is indicated for the prevention of COPD exacerbations.

Asthma.

Spiriva Respimat is indicated as add-on maintenance bronchodilator treatment in patients aged 6 years and older with moderate to severe asthma.

4.2 Dose and Method of Administration

Spiriva Respimat is for oral inhalation only.
The recommended dose of tiotropium using the Spiriva Respimat is 5 micrograms. This is administered as two puffs once daily at the same time each day (see Section 4.2 Dose and Method of Administration, Instructions for use and handling).
The recommended dose should not be exceeded.
In the treatment of asthma, the full benefits will be apparent after several doses of Spiriva Respimat.

Paediatric population.

In asthma, the recommended dose of tiotropium using the Spiriva Respimat in patients 6 to 17 years of age is 5 micrograms. This is administered as two puffs once daily from the Respimat re-usable inhaler, at the same time each day (see Section 4.2 Dose and Method of Administration, Instructions for use and handling).

Elderly.

Elderly patients can use Spiriva Respimat at the recommended dose.

Patients with renal impairment.

Renally impaired patients can use Spiriva Respimat at the recommended dose. However, as with all predominantly renally excreted drugs, Spiriva Respimat use should be monitored closely in patients with moderate to severe renal impairment.

Patients with hepatic impairment.

Hepatically impaired patients can use Spiriva Respimat at the recommended dose.

Instructions for use and handling.

To ensure proper administration of Spiriva Respimat, the patient should be shown how to use the Spiriva Respimat re-usable inhaler by a physician or other health professional (see Respimat re-usable inhaler Instructions for Use).

4.3 Contraindications

Spiriva Respimat is contraindicated in patients with a history of hypersensitivity to tiotropium bromide, atropine or its derivatives, e.g. ipratropium or oxitropium or to any other component of this product (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Benzalkonium chloride may cause wheezing and breathing difficulties. Patients with asthma are at an increased risk for these adverse events.
Spiriva Respimat, as a once daily maintenance bronchodilator, should not be used for the treatment of acute episodes of bronchospasm or for the relief of acute symptoms. In the event of an acute attack, a rapid-acting beta-2-agonist should be used.
Spiriva Respimat should not be used as a first-line treatment for asthma. Patients with asthma must be advised to continue taking anti-inflammatory therapy, i.e. inhaled corticosteroids, unchanged after the introduction of Spiriva Respimat, even when their symptoms improve.
Immediate hypersensitivity reactions may occur after administration of Spiriva Respimat solution for inhalation.
As with other anticholinergic drugs, Spiriva Respimat should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction. In a meta-analysis of placebo-controlled trials, Spiriva was associated with a non-significant increase in the risk of urinary retention, and a significant increase in the risk of micturition difficulties.
Dry mouth, which has been observed with anticholinergic treatment, may in the long term be associated with dental caries.
Inhaled medicines may cause inhalation-induced bronchospasm.
Tiotropium should be used with caution in patients with recent myocardial infarction < 6 months; any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy in the past year; hospitalisation of heart failure (NYHA Class III or IV) within the past year. These patients were excluded from the clinical trials and these conditions may be affected by the anticholinergic mechanism of action.
As with all predominantly renally excreted drugs, Spiriva use should be monitored closely in patients with moderate to severe renal impairment (creatinine clearance of ≤ 50 mL/min) (see Section 5.2 Pharmacokinetic Properties). There is no long term experience in patients with severe renal impairment.
Patients must be instructed in the correct administration of Spiriva. Care must be taken not to allow the solution or mist to enter into the 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 narrow-angle glaucoma. Should any combination of these symptoms develop specialist advice should be sought immediately. Miotic eye drops are not considered to be effective treatment.
Spiriva Respimat should not be used more frequently than once daily (see Section 4.9 Overdose).
Spiriva cartridges are to be used only with Respimat re-usable inhaler (see Respimat re-usable inhaler Instructions for Use).

Paediatric use.

COPD does not normally occur in children.
In children aged 1-5 years: One 12-week clinical study was conducted in a total of 101 children with asthma on background treatment of at least ICS.
An Aerochamber Plus Flow-Vu valved holding chamber with facemask was used to administer trial medication in 98 patients.
The primary objective of the study was safety; efficacy assessments were exploratory.
There was no difference in the exploratory symptoms score in those treated with tiotropium versus placebo. The number of asthma adverse events was lower for Spiriva Respimat compared to placebo.
Tiotropium has not been studied in children less than 1 year.

Use in the elderly.

Elderly patients can use Spiriva Respimat at the recommended dose. Renal clearance of tiotropium is likely to be slower in elderly patients (see Use in renal impairment).

Use in hepatic impairment.

There are no data on the use of tiotropium in patients with hepatic impairment. As tiotropium is primarily cleared by renal mechanisms, no dosage adjustment is recommended. However patients should be monitored closely.

Use in renal impairment.

Renally-impaired patients can use Spiriva Respimat at the recommended dose. However, as with all predominantly renally excreted drugs, Spiriva Respimat use should be monitored closely in COPD and asthma patients with moderate to severe renal impairment (creatinine clearance ≤ 50 mL/min).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Although no formal drug interaction studies have been performed, tiotropium bromide has been used concomitantly with other drugs which are commonly used in the treatment of COPD and asthma, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, antihistamines, mucolytics, leucotriene modifiers, cromones and anti-IgE treatment without clinical evidence of drug interactions.
Common concomitant medications (LABA, ICS and their combinations) used by patients with COPD were not found to alter the exposure to tiotropium.
Limited information about co-administration of other anticholinergic medicines with Spiriva is available from a clinical trial. The concomitant use of Spiriva Respimat with other anticholinergic agents (e.g. glycopyrronium, aclidinium, umeclidinium, ipratropium) is expected to have additive anticholinergic effects. Acute single dose administration of ipratropium bromide after 19 days of Spiriva treatment in healthy volunteers (n=35) was not associated with relevant changes in vital signs or electrocardiographic findings. Adverse events were reported by 3 (9%) of subjects in the study during ipratropium treatment with tiotropium compared to 1 (3%) during placebo treatment with tiotropium. Ipratropium was associated with a 16% decrease in salivary secretions in healthy volunteers. The chronic co-administration of tiotropium bromide with other anticholinergic medicines has not been studied. Therefore, the chronic co-administration of other anticholinergic drugs with Spiriva Respimat is not recommended.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Clinical data on fertility are not available for tiotropium. Tiotropium (as bromide) did not affect the fertility of male or female rats when administered by inhalation at doses up to 2 mg/kg (750x the maximum recommended human daily dose of the drug, based on body surface area).
(Category B1)
There is a limited amount of data from the use of tiotropium in pregnant women. Reproductive toxicity studies with tiotropium bromide administered by inhalation to rats and rabbits at doses up to 2.0 and 0.5 mg/kg/day, respectively, produced no evidence of fetal malformations. These doses correspond to 750x and 400x the maximum recommended human daily dose of the drug based on body surface area. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses.
As a precautionary measure, it is preferable to avoid the use of Spiriva Respimat during pregnancy.
In juvenile rats exposed from postnatal day 7 to sexual maturity, the same direct and indirect pharmacological changes were observed as in the repeat-dose toxicity studies as well as rhinitis. No systemic toxicity was noted and no toxicologically relevant effects on key developmental parameters, tracheal or key organ development were seen.
 Clinical data from lactating women exposed to tiotropium are not available. Based on studies in lactating rats, a small amount of tiotropium is excreted in breast milk.
Therefore, Spiriva Respimat should not be used in lactating women unless the expected benefit outweighs any possible risk to the infant.

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. The occurrence of dizziness or blurred vision may influence the ability to drive and use 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 http://www.tga.gov.au/reporting-problems.
Many of the listed adverse effects can be assigned to the anticholinergic properties of Spiriva Respimat.
Adverse drug reactions were identified from data obtained in clinical trials and spontaneous reporting during post approval use of the drug.
The clinical trial database for COPD includes 3,282 Spiriva Respimat patients from 7 placebo-controlled clinical trials with treatment periods ranging between four weeks and one year, contributing 2,440 person years of exposure.
The clinical trial database for asthma includes 1,930 tiotropium treated patients from 12 placebo controlled trials with treatment period ranging between twelve weeks and one year, contributing 1,128 person years of exposure to tiotropium.
Frequency is defined using the following convention:
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), not known (cannot be estimated from the available data). See Table 1.

Description of selected adverse effects.

In controlled clinical studies of COPD, the commonly observed adverse effects were anticholinergic undesirable effects such as dry mouth which occurred in approximately 2.9% of patients. In asthma the incidence of dry mouth was 0.83%.
Serious adverse effects consistent with anticholinergic effects include glaucoma, constipation, intestinal obstruction (including paralytic ileus) and urinary retention.
An increase in anticholinergic effects may occur with increasing age.

Paediatric population.

The frequency, type, and severity of adverse reactions in the paediatric population are similar as in adults.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).
High doses of tiotropium may lead to anticholinergic signs and symptoms.
However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 micrograms tiotropium in healthy volunteers. Additionally, no relevant adverse effects, beyond dry mouth, were observed following 7 day dosing of up to 141 micrograms tiotropium in healthy volunteers. In a multiple dose study in patients with COPD, with a maximum daily dose of 36 micrograms tiotropium over four weeks, no significant undesirable effects were observed.
No relevant adverse events, beyond dry mouth/throat and dry nasal mucosa, were observed following 14-day dosing of up to 40 micrograms tiotropium solution for inhalation in healthy subjects with the exception of pronounced reduction in salivary flow from day 7 onwards. No significant undesirable effects have been observed in six long-term studies in patients with COPD when a daily dose of 10 micrograms tiotropium solution for inhalation was given over 4-48 weeks.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, anticholinergics; ATC code: R03B B04.

Mechanism of action.

Tiotropium is a long-acting, specific antimuscarinic (anticholinergic) agent. It has similar affinity to the muscarinic receptor subtypes M1 to M5 (KD 5-41 pM). In the airways, inhibition by tiotropium of M3-receptors at the smooth muscle results in relaxation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors. In non-clinical in vitro as well as in vivo studies, bronchoprotective effects were dose-dependent. Bronchoprotective effects lasting at least 24 hours were observed in some of the in vivo studies. The long duration of effect of tiotropium is likely to be due to its slow dissociation from M3-receptors. Tiotropium exhibited a significantly longer dissociation half-life from M3 receptors than ipratropium.
Tiotropium, a N-quaternary anticholinergic agent, is topically (broncho-) selective when administered by inhalation. The high potency (IC50 approximately 0.4 nanoM for M3) and slow receptor dissociation is associated with a significant and long-acting bronchodilation in patients with chronic obstructive pulmonary disease (COPD) and asthma.
The bronchodilation following inhalation of tiotropium is primarily a local effect on the airways, not a systemic one.

Clinical trials.

COPD.

The clinical Phase III programme for COPD included two 1-year, two 12-week and two 4-week randomised, double-blind studies in 2901 patients with COPD (1038 receiving the 5 micrograms tiotropium dose). The 1-year programme consisted of two placebo-controlled trials. The two 12-week trials were both active (ipratropium) - and placebo-controlled. All six studies included lung function measurements, with trough FEV1 (i.e. FEV1 measured approximately 10 minutes before the final dose) as the primary endpoint. In addition, the two 1-year studies included health outcome measures of health-related quality of life, dyspnoea, and effect on exacerbations as co-primary endpoints.
Placebo-controlled studies.

Lung function.

Spiriva Respimat administered once daily, provided significant improvement in lung function (forced expiratory volume in one second and forced vital capacity) within 30 minutes following the first dose, compared to placebo. Improvement of lung function was maintained for 24 hours at steady state. Pharmacodynamic steady state was reached within one week.
Mean trough FEV1 treatment difference for Spiriva Respimat over placebo in the combined 1-year trials at day 337 was 127 mL (p < 0.0001 vs. placebo). Improvement of lung function was maintained for 24 hours at steady state. Pharmacodynamic steady state was reached within one week. The bronchodilator effects of Spiriva Respimat were maintained throughout the 48-week period of administration with no evidence of tolerance.
Mean trough FEV1 treatment differences for the combined 12-week trials at day 85 was 118 mL for Spiriva Respimat over placebo (p < 0.0001) and 64 mL for Spiriva Respimat over ipratropium bromide (p=0.0060).
A combined analysis of two randomised, placebo-controlled, crossover, clinical studies demonstrated that the bronchodilator response as measured by mean trough FEV1 for Spiriva Respimat was 29 mL higher than Spiriva HandiHaler (18 micrograms) inhalation powder after a 4-week treatment period (p=0.03). Since steady state efficacy is reached within 4 weeks, no longer term study comparing the two products has been conducted.
Spiriva Respimat significantly improved morning and evening PEFR (peak expiratory flow rate) as measured by patient's daily recordings (morning improvement mean 22 L/min, p < 0.0001; evening improvement mean 26 L/min, p < 0.0001). The use of Spiriva Respimat resulted in a reduction of rescue bronchodilator use compared to placebo.

Dyspnoea, health-related quality of life, COPD exacerbations in long-term 1 year studies.

(a) Spiriva Respimat significantly improved dyspnoea (as evaluated using the Transition Dyspnoea Index) the magnitude of change being 1.05 units at day 337 (p < 0.0001 vs. placebo). The mean Baseline Dyspnoea Index was 6.41 units. Improvement was maintained throughout the treatment period.
(b) Patients' evaluation of their Quality of Life (as measured using the St. George's Respiratory Questionnaire) showed that Spiriva Respimat had positive effects on the psychosocial impacts of COPD, activities affected by COPD and distress due to COPD symptoms.
The improvement in mean total score between Spiriva Respimat versus placebo at the end of the two 1-year studies was statistically significant and maintained throughout the treatment period. By day 337 the mean treatment difference improvement in SGRQ total score from placebo (pooled data from the two 1-year studies) was 3.5 for Spiriva Respimat (p < 0.0001 vs. placebo). The mean SGRQ total score at baseline was 44.8.
(c) COPD exacerbations.
In three one-year, randomised, double-blind, placebo-controlled clinical trials Spiriva Respimat treatment resulted in a significantly reduced risk of a COPD exacerbation in comparison to placebo. Exacerbations of COPD were defined as "a complex of at least two respiratory events/symptoms with a duration of three days or more requiring a change in treatment (prescription of antibiotics and/or systemic corticosteroids and/or a significant change of the prescribed respiratory medication)". Spiriva Respimat treatment resulted in a reduced risk of a hospitalisation due to a COPD exacerbation (significant in the appropriately powered large exacerbation trial).
The pooled analysis of two Phase III trials and separate analysis of an additional exacerbation trial is displayed in Table 2. All respiratory medications except anticholinergics and long-acting beta-agonists were allowed as concomitant treatment, i.e. rapidly acting beta-agonists, inhaled corticosteroids and xanthines. Long-acting beta-agonists were allowed in addition in the exacerbation trial.
Long-term tiotropium active-controlled study. A long term, large scale, randomised, double-blind, active-controlled study with an observation period up to 3 years has been performed to compare the efficacy and safety of Spiriva Respimat and Spiriva HandiHaler (5,711 patients receiving Spiriva Respimat 2.5 microgram (2 puffs comprise one medicinal dose of 5 micrograms); 5,694 patients receiving Spiriva HandiHaler). The primary endpoints were time to first COPD exacerbation, time to all-cause mortality and in a sub-study (906 patients) trough FEV1 (pre-dose).
The time to first COPD exacerbation was similar during the study with Spiriva Respimat and Spiriva HandiHaler (hazard ratio (Spiriva Respimat/ Spiriva HandiHaler) 0.98 with a 95% CI of 0.93 to 1.03).
The median number of days to the first COPD exacerbation was 756 days for Spiriva Respimat and 719 days for Spiriva HandiHaler.
The bronchodilator effect of Spiriva Respimat was sustained over 120 weeks, and was similar to Spiriva HandiHaler. The mean difference in trough FEV1 for Spiriva Respimat versus Spiriva HandiHaler was -0.010 L (95% CI -0.038 to 0.018 L).
All-cause mortality was similar during the study with Spiriva Respimat and Spiriva HandiHaler (hazard ratio (Spiriva Respimat/ Spiriva HandiHaler) 0.96 with a 95% CI of 0.84 to 1.09).

Asthma.

Adult patients.

The clinical Phase III programme for persistent asthma included two 48 week, two 6-month and one 12-week, randomised, double-blind, placebo-controlled studies in a total of 3,476 asthma patients (1,128 receiving Spiriva Respimat, tiotropium 5 microgram, once daily) on background treatment of at least ICS or ICS/LABA. The two 6-month studies were also active-controlled (salmeterol). All 5 studies included lung function measurements, assessments of symptoms including exacerbations, and health-related quality of life.
In the two 48-week PrimoTinA-asthma studies in patients who were symptomatic on maintenance treatment of at least high-dose ICS plus LABA, Spiriva Respimat showed significant improvements in lung function over placebo when used as add-on to background treatment.
At week 24, mean improvements in peak and trough FEV1 were 0.110 litres (95% CI: 0.063 to 0.158 litres, p < 0.0001) and 0.093 litres (95% CI: 0.050 to 0.137 litres, p < 0.0001), respectively.
The improvement of lung function compared to placebo was maintained for 24 hours (Figure 1).
At week 24, Spiriva Respimat significantly improved morning and evening peak expiratory flow (PEF; mean improvement in the morning 23 L/min; 95% CI: 16 to 29 L/min, p < 0.0001; evening 26 L/min; 95% CI: 20 to 33 L/min, p < 0.0001).
The bronchodilator effects of Spiriva Respimat were maintained throughout the 48-week period of administration with no evidence of tachyphylaxis or tolerance (Figure 2).
Spiriva Respimat significantly reduced the risk of severe asthma exacerbations (see Table 3 and Figure 3).
The Asthma Control Questionnaire (ACQ) responder rates, defined as percentage of patients improving by at least 0.5 points, were significantly higher with Spiriva Respimat (53.9% versus 46.9%; p=0.0427).
The Asthma Quality of Life Questionnaire (AQLQ(S)) mean scores for Spiriva Respimat improved significantly over placebo at week 24 (treatment difference: 0.117, 95% CI: 0.011, 0.223, p=0.0312).
In the two 6-month MezzoTinA-asthma studies in patients who were symptomatic on maintenance treatment of medium-dose ICS, Spiriva Respimat showed significant improvements in lung function over placebo when used as add-on to background treatment.
At week 24, mean improvements in peak and trough FEV1 were 0.185 litres (95% CI: 0.146 to 0.223 litres, p < 0.0001) and 0.146 litres (0.105 to 0.188 litres, p < 0.0001), respectively. The peak and trough FEV1 values for salmeterol were 0.196 litres (95% CI: 0.158 to 0.234 litres) and 0.114 litres (95% CI: 0.073 to 0.155 litres), respectively.
Spiriva Respimat significantly improved morning and evening PEF (morning 24 L/min; 95% CI: 18 to 31 L/min, p < 0.0001; evening 23 L/min; 95% CI: 17 to 30 L/min, p < 0.0001). The morning and evening PEF for salmeterol compared to placebo were 25 L/min (95% CI: 19 to 31 L/min) and 21 L/min (95% CI: 15 to 27 L/min), respectively.
Patients who took Spiriva Respimat had a significantly higher ACQ responder rate at week 24 compared to patients taking placebo (Table 4).
In the 12 week GraziaTinA-asthma study in patients who were symptomatic on maintenance treatment with low dose ICS, Spiriva Respimat showed significant improvements in lung function over placebo when used as add-on to background treatment. At 12 weeks, the mean improvements in peak and trough FEV1 were 0.128 litres (95% CI: 0.057 to 0.199 litres, p < 0.0005) and 0.122 litres (95% CI: 0.049 to 0.194 litres, p < 0.0010), respectively.

Paediatric patients.

The clinical phase III program for persistent asthma in paediatric patients (1-17 years) was based on the following clinical trials and a partial extrapolation of data from adults:
Adolescents (12-17 years): one 1-year and one 12-week randomised, double-blind, placebo-controlled studies in a total of 789 asthma patients (264 receiving Spiriva Respimat, tiotropium 5 microgram, once daily).
Children (6-11 years): one 1-year and one 12-week randomised, double-blind, placebo-controlled studies in a total of 801 asthma patients (265 receiving Spiriva Respimat tiotropium 5 microgram, once daily).
Children (1-5 years): one 12-week randomised, double-blind placebo-controlled study in a total of 101 asthma patients (31 receiving Spiriva Respimat tiotropium 5 microgram, once daily).
In all these studies, patients were on background treatment of at least ICS.

Adolescents (12-17 years).

In the 1-year RubaTinA-asthma study in patients with moderate asthma who were symptomatic on maintenance treatment of at least medium-dose ICS, Spiriva Respimat showed significant improvements in lung function over placebo when used as add-on to background treatment.
At week 24, mean improvements in peak and trough FEV1 were 0.174 litres (95% CI: 0.076 to 0.272 litres, p=0.0005) and 0.117 litres (95% CI: 0.010 to 0.223 litres, p=0.0320), respectively.
At week 24, Spiriva Respimat significantly improved morning and evening PEF (morning 15.8 L/min; 95% CI: 2.3, 29.3 L/min, p=0.0214; evening 16.7 L/min; 95% CI: 3.4, 30.0 L/min, p=0.0137).
The bronchodilator effects of Spiriva Respimat were maintained throughout the 1 year period of administration with no evidence of tachyphylaxis (Figure 4).
In the 12-week PensieTinA-asthma study in patients with severe asthma who were symptomatic on maintenance treatment of at least medium dose ICS in combination with 1 or more controller medication (e.g. LABA), Spiriva Respimat showed improvements in lung function over placebo when used as add-on to background treatment, however, the differences in peak and trough FEV1 were not statistically significant.
At week 12, mean improvements in peak and trough FEV1 were 0.090 litres (95% CI: -0.019 to 0.198 litres, p=0.1039) and 0.054 litres (95% CI: -0.061 to 0.168 litres, p=0.3605), respectively.
At week 12, Spiriva Respimat significantly improved morning and evening PEF (morning 17.4 L/min; 95% CI: 5.1 to 29.6 L/min; evening 17.6 L/min; 95% CI: 5.9 to 29.6 L/min).

Children (6-11 years).

In the 1-year CanoTinA-asthma study in patients with moderate asthma who were symptomatic on maintenance treatment of at least medium-dose ICS, Spiriva Respimat showed significant improvements in lung function over placebo when used as add-on to background treatment.
At week 24, mean improvements in peak and trough FEV1 were 0.164 litres (95% CI: 0.103 to 0.225 litres, p < 0.0001) and 0.118 litres (95% CI: 0.048 to 0.188 litres, p=0.0010), respectively.
The bronchodilator effects of Spiriva Respimat were maintained throughout the 1 year period of administration with no evidence of tachyphylaxis (Figure 5).
In the 12-week VivaTinA-asthma study in patients with severe asthma who were symptomatic on maintenance treatment of at least medium dose ICS in combination with 1 or more controller medication (e.g. LABA), Spiriva Respimat showed significant improvements in lung function over placebo when used as add-on to background treatment.
At week 12, mean improvements in peak and trough FEV1 were 0.139 litres (95% CI: 0.075 to 0.203 litres, p < 0.0001) and 0.087 litres (95% CI: 0.019 to 0.154 litres, p=0.0117), respectively.

5.2 Pharmacokinetic Properties

Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium bromide is available as solution for inhalation administered by the Respimat re-usable inhaler. Generally with the inhaled route of administration, the majority of the delivered dose is swallowed and deposited in the gastrointestinal tract, and to a lesser extent is delivered to the lungs. Approximately 40% of the inhaled dose of tiotropium Respimat is deposited in the lungs, the target organ, the remaining amount being deposited in the gastrointestinal tract. Some of the tiotropium Respimat pharmacokinetic data described below were obtained with higher doses than recommended for therapy.

Bioequivalence.

The primary objective of the Phase II, crossover study 205.458 involving 123 patients with COPD was to compare the pharmacokinetics of 5 microgram tiotropium solution for inhalation delivered by the Respimat Inhaler (Tio R 5) with tiotropium powder for inhalation 18 microgram delivered by the HandiHaler (Tio HH 18). The exposure to tiotropium following the use of Tio R 5 was lower compared to Tio HH 18. Using the parameters AUC0‐6,ss and Cmax,ss, bioequivalence was not established between Tio R 5 and Tio HH 18. The ratio of AUC0‐6,ss (Tio R 5/ Tio HH 18) was 75.99% (90% confidence interval of (70.44, 81.98)). The ratio of Cmax,ss was 80.66% (90% CI: 73.49, 88.52).

Absorption.

Following inhalation by young healthy volunteers, urinary excretion data suggests that approximately 33% of the inhaled dose reaches the systemic circulation. It is expected from the chemical structure of the compound that tiotropium is poorly absorbed from the gastro-intestinal tract. This was confirmed in a study in young healthy volunteers, with a low bioavailability of 2-3% for oral solutions. Food is not expected to influence the absorption of tiotropium for the same reason. Maximum tiotropium plasma concentrations were observed 5-7 minutes after inhalation. At steady state, peak tiotropium plasma concentrations of 10.5 picogram/mL were achieved in patients with COPD and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 1.60 picogram/mL. A steady state tiotropium peak plasma concentration of 5.15 picogram/mL was attained 5 minutes after the administration of the same dose to patients with asthma.

Distribution.

The drug has a plasma protein binding of 72% and shows a volume of distribution of 32 L/kg.
Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium does not penetrate the blood-brain barrier to any relevant extent.

Metabolism.

Metabolism does not occur to any great extent in young healthy volunteers, as indicated by 74% renal excretion of unchanged drug after an intravenous dose. The major metabolic pathway is non-enzymatic ester cleavage to the alcohol N-methylscopine and dithienylglycolic acid that are inactive on muscarinic receptors.
In vitro metabolism: In studies in animals and in vitro experiments with human liver microsomes and hepatocytes, minor amounts of a variety of glutathione conjugates, after oxidation of the thiophene rings, were observed.
In vitro studies in human liver microsomes revealed that the enzymatic pathway, relevant for only a small amount of tiotropium metabolism, can be inhibited by cytochrome P450 (CYP) 2D6 inhibitor quinidine and CYP3A4 inhibitors ketoconazole and gestodene.
Tiotropium, even in supra-therapeutic concentrations, does not inhibit CYP1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.

Excretion.

The effective half-life of tiotropium ranges between 27 to 45 h following inhalation by patients with COPD or asthma.
The effective half-life was 34 hours in patients with asthma.
Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers. Urinary excretion of unchanged substance in young healthy volunteers is 74% of an intravenous dose. After inhalation of the solution for inhalation by patients with COPD, urinary excretion is 18.6% (0.93 microgram) of the dose, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces.
In patients with asthma, 11.9% (0.595 microgram) of the dose is excreted unchanged in the urine over 24 hours post dose at steady state.
The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine. After chronic, once daily inhalation, pharmacokinetic steady state was reached by day 7, with no accumulation thereafter.
Tiotropium demonstrates linear pharmacokinetics in the therapeutic range, independent of the formulation.

Special populations.

Elderly patients.

As expected for all predominantly renally excreted drugs, advancing age was associated with a decrease of tiotropium renal clearance from 347 mL/min in patients with COPD < 65 years to 275 mL/min in patients with COPD ≥ 65 years. This did not result in a corresponding increase in AUC0-6,ss and Cmax,ss values.
Exposure to tiotropium was not found to differ with age in patients with asthma.

Paediatric patients.

The peak and total exposure to tiotropium was not found to differ between paediatric patients (aged 6 to 17 years) and adults with asthma. In patients 1 to 5 years old with asthma (n=3), the total exposure as measured by urinary excretion (over 3 hours) was 52 to 60% lower than that observed in patients 6 years and older with asthma; the total exposure data when adjusted for body surface area were found to be comparable in all age groups. Spiriva Respimat was administered with a valved holding chamber with facemask in patients 1 to 5 years of age.

Renally impaired patients.

Following once daily inhaled administration of tiotropium to steady-state to patients with COPD with mild renal impairment (CLCR 50-80 mL/min) resulted in slightly higher AUC0-6,ss (between 1.8 to 30% higher) and similar Cmax,ss compared to COPD patients with normal renal function (CLCR > 80 mL/min). In patients with COPD with moderate to severe renal impairment (CLCR < 50 mL/min), the intravenous administration of tiotropium resulted in a doubling of the total exposure (82% higher AUC0-4h and 52% higher Cmax) compared to patients with COPD with normal renal function, which was confirmed by plasma concentrations after dry powder inhalation.
In asthma patients with mild renal impairment (CLCR 50-80 mL/min) inhaled tiotropium did not result in relevant increases in exposure compared to patients with normal renal function.

Hepatically impaired patients.

There are no data on the pharmacokinetics of tiotropium in hepatic impairment. Liver insufficiency is not expected to have any relevant influence on tiotropium pharmacokinetics. Tiotropium is predominantly cleared by renal elimination (74% in young healthy volunteers) and by simple non-enzymatic ester cleavage to products that do not bind to muscarinic receptors.

5.3 Preclinical Safety Data

Genotoxicity.

Tiotropium (as bromide) did not exhibit any genotoxic effects in assays for gene mutation (bacteria and mammalian cells in vitro and in vivo mouse micronucleus test) or DNA damage (rat hepatocytes in vitro).

Carcinogenicity.

Long-term carcinogenicity studies in mice and rats, with tiotropium (as bromide) administered by inhalation, showed no evidence of neoplastic responses. The highest doses studied were approximately 0.8x (male mouse), 38x (female mouse) and 1x (rat) greater than the maximum recommended human daily dose of the drug, based on body surface area.

6 Pharmaceutical Particulars

6.1 List of Excipients

Excipients include benzalkonium chloride, disodium edetate, purified water, and hydrochloric acid for pH adjustment.

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.
Spiriva Respimat cartridge should be used within 3 months after insertion in the Spiriva Respimat re-usable inhaler.
The in-use shelf-life of the re-usable inhaler is 1 year.
Recommended use per re-usable inhaler is 6 cartridges.

6.4 Special Precautions for Storage

Store below 25°C in a safe place out of the reach of children. Do not freeze.

6.5 Nature and Contents of Container

Type and material of the container in contact with the medicinal product:
Solution filled into a polyethylene/polypropylene cartridge with a polypropylene cap with integrated silicone sealing ring. The cartridge is enclosed within an aluminium cylinder.
Pack sizes and devices supplied:
Single pack: 1 Spiriva Respimat re-usable inhaler and 1 Spiriva Respimat cartridge, providing 60 puffs (30 doses).
Triple pack: 1 Spiriva Respimat re-usable inhaler and 3 Spiriva Respimat cartridges, providing 60 puffs (30 doses) each.
Single refill pack: 1 Spiriva Respimat cartridge, providing 60 puffs (30 doses).
Triple refill pack: 3 Spiriva Respimat cartridges, providing 60 puffs (30 doses) each.
Not all pack sizes may be marketed.

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

Tiotropium bromide is a white to yellowish-white, odourless crystalline powder. It exists as a quaternary ammonium salt, and there are no ionisable functional groups on the molecule. The active substance is not optically active.
Tiotropium bromide is freely soluble in dimethyl sulphoxide, soluble in methanol, sparingly soluble in water and practically insoluble in methylene chloride. The solubility in aqueous solutions at room temperature is approx. 2.5%, independent of pH. At pH 7.4, the apparent partition coefficient (log Papp) is -2.25.
A monohydrate form of tiotropium bromide is produced by the synthetic process. The compound melts with decomposition between 225°C and 235°C, when determined by differential scanning calorimetry at a heating rate of 10 K per minute.

Chemical structure.

Chemical name: 3-Oxa-9-azoniatricyclo[3.3.1.02,4]nonane, 7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-, bromide, monohydrate, (1α, 2β, 4β, 5α, 7β).
Molecular formula: C19H22NO4S2Br.H2O.
Molecular weight: 490.4 (monohydrate).
Structural formula:

CAS number.

139404-48-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes