Consumer medicine information

Spiriva Respimat

Tiotropium bromide

BRAND INFORMATION

Brand name

Spiriva Respimat Solution for inhalation

Active ingredient

Tiotropium bromide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Spiriva Respimat.

What is in this leaflet

This leaflet answers some common questions about Spiriva Respimat.

It does not contain all the available information.

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

All medicines have risks and benefits. Your doctor has weighed the risks of you using Spiriva Respimat against the benefits they expect it will have for you.

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

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

Keep this leaflet with the medicine.

You may need to read it again.

What Spiriva Respimat is used for

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

  • chronic obstructive pulmonary disease (COPD)
  • asthma.

When used to treat asthma you should use Spiriva Respimat in addition to other medicines called inhaled corticosteroids and long- acting beta-2-agonists.

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 to prevent exacerbations (periodic worsening of symptoms) from occurring.

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 or other irritants.

Spiriva Respimat improves breathing by relaxing the breathing tubes or air passages that carry air to and from the lungs.

Spiriva Respimat contains the active ingredient tiotropium bromide monohydrate. It belongs to a group of medicines called anticholinergics.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

Before you use Spiriva Respimat

When you must not use it

Do not use Spiriva Respimat if you have an allergy to:

  • any medicine containing tiotropium bromide
  • any of the ingredients listed at the end of this leaflet
  • any medicine containing atropine or its derivatives, e.g. ipratropium or oxitropium
  • any other anticholinergic medicines.

Symptoms of an allergic reaction may include:

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

Do not use Spiriva Respimat to treat an acute asthma attack or sudden attack of breathlessness, wheezing or coughing.

You will need a different type of medicine for this.

Do not give Spiriva Respimat to children or adolescents (below the age of 18 years).

Do not use this medicine after the expiry date printed on the inhaler label or carton, or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start using this medicine, talk to your doctor.

Before you start to use it

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

Tell 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 with 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.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding.

Your doctor can discuss with you the risks and benefits involved. Spiriva is not generally recommended for use in pregnant women.

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.

Use this medicine only with the Respimat device.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any 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.

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

Your doctor or pharmacist have more information on medicines to be careful with or avoid while using this medicine.

How to use Spiriva Respimat

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

They may differ from the information contained in this leaflet.

If you have been prescribed Spiriva Respimat for your asthma it should be added on to inhaled corticosteroids and long-acting beta-2-agonists.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to use

Take 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.

How to use it

Spiriva Respimat is for inhalation use only.

Make sure that you know how to use your Spiriva Respimat inhaler properly.

The instructions for use are provided at the end of this leaflet.

Carefully read the instructions for use and follow the diagrams that show you how to use the Spiriva Respimat inhaler.

If you do not understand the instructions on how to use the Spiriva Respimat inhaler, ask your doctor or pharmacist for help.

Use the Spiriva Respimat 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 inhaler to prepare the inhaler for first use.

The Spiriva Respimat 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.

When to use it

Use your medicine at about the same time each day.

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

How long to use it

Continue to use Spiriva Respimat for as long as your doctor tells you.

Spiriva Respimat helps to control your condition but it does not cure it. Therefore you must use Spiriva Respimat every day. It is important to keep taking your medicine even if you feel well.

If you forget to use it

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 that you missed.

This may increase the chance of you getting an unwanted side effect.

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

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

If you use too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre 13 11 26 for advice, or go to Emergency at your nearest hospital, if you think that you or anyone else may have used too much Spiriva Respimat. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Symptoms of an overdose may include fast or irregular heartbeat, blurred vision, nausea, stomach pain, dry mouth, constipation, difficulty passing urine.

While you are using Spiriva Respimat

Things you must do

If you are about to be started on any new medicine, remind your doctor or pharmacist that you are using Spiriva Respimat.

Tell any other doctors, dentists and pharmacists who are treating you that you are using this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

It may affect other medicines used during surgery.

If you become pregnant while using this medicine, tell your doctor immediately.

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 an 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 should be added on to inhaled corticosteroids and long-acting beta-2-agonists. Continue taking the inhaled corticosteroids as prescribed by your doctor, even if you feel better.

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.

Things you must not do

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.

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.

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 COPD may worsen.

Do not take Spiriva Respimat more frequently than once daily.

Things to be careful of

Be careful when driving or operating machinery 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.

Pay attention to oral hygiene.

Dry mouth which has been observed with anticholinergic treatment may in the long term be associated with tooth decay.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Spiriva Respimat.

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

Do not be alarmed by the following lists of side effects.

You may not experience any of them.

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

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

  • dry mouth: this is usually mild
  • sore mouth, gums, or throat; swollen, red, sore tongue
  • oral thrush
  • hoarse voice
  • nose bleeds
  • cough
  • dry skin
  • skin infection or skin ulcer
  • dizziness
  • trouble sleeping.

Tell your doctor as soon as possible if you notice any of the following:

  • blurred vision
  • seeing halos around lights or coloured images in association with red eyes; high pressure in the eye (glaucoma)
  • difficulty in swallowing
  • heartburn
  • difficulty or pain when passing urine, urinary tract infection, increased need and frequency in passing urine
  • constipation
  • 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.

The above list includes serious side effects that may require medical attention.

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

  • fast or irregular heartbeats, palpitations
  • 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.

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

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

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

After using Spiriva Respimat

Care and cleaning

Follow the instructions at the end of this leaflet 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.

Storage

Keep Spiriva Respimat in a cool dry place where the temperature stays below 25°C. Do not freeze.

Do not store Spiriva Respimat or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Discard Spiriva Respimat inhaler 3 months after inserting the Spiriva Respimat cartridge into the Spiriva Respimat inhaler even if it contains some unused medicine, or when the inhaler is locked (after 60 puffs), whichever comes first.

Disposal

If your doctor tells you to stop using this medicine, or the expiry date has passed, or it has been more than 3 months after its first use, or if the inhaler has locked (after 60 puffs), ask your pharmacist how to dispose of it properly.

Product Description

What it looks like

Spiriva Respimat is composed of one cartridge with solution for inhalation and one Respimat inhaler. The cartridge has to be inserted into the inhaler before first use.

Each pack consists of:

  • one Respimat inhaler (with a green-coloured cap) and
  • one Spiriva Respimat cartridge providing 60 puffs (equal to 30 doses of medicine).

Ingredients

Spiriva Respimat contains 2.5 micrograms tiotropium (as bromide monohydrate) per puff.

It also contains:

  • benzalkonium chloride
  • disodium edetate
  • purified water
  • hydrochloric acid for pH adjustment.

Supplier

Spiriva Respimat is supplied in Australia by:

Boehringer Ingelheim Pty Limited
ABN 52 000 452 308
78 Waterloo Road
NORTH RYDE NSW 2113

This leaflet was revised in September 2016.

Spiriva® and Respimat® are registered trademarks of Boehringer Ingelheim

© Boehringer Ingelheim Pty Limited 2016

Australian Registration Number:

AUST R 132578

Instructions for Use

Introduction

Read these Instructions for Use before you start using Spiriva Respimat (tiotropium bromide monohydrate).

You will need to use this inhaler only ONCE A DAY. Each time you use it take TWO PUFFS.

How to store my Spiriva Respimat

  • Keep your Spiriva Respimat out of the sight and reach of children.
  • Do not freeze your Spiriva Respimat.
  • If Spiriva Respimat has not been used for more than 7 days release one puff towards the ground.
  • If Spiriva Respimat has not been used for more than 21 days repeat steps 4 to 6 under ‘Prepare for first use’ until a cloud is visible. Then repeat steps 4 to 6 three more times.
  • Do not use your Spiriva Respimat after the expiry date.
  • Do not touch the piercing element inside the clear base.

How to care for 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.

Any minor discoloration in the mouthpiece does not affect your Spiriva Respimat inhaler performance.

When to get a new Spiriva Respimat

  • Your Spiriva Respimat inhaler contains 60 puffs (30 doses) if used as indicated (two puffs/once daily).
  • The dose indicator shows approximately how much medication is left.
  • When the dose indicator enters the red area of the scale you need to get a new prescription; there is approximately medication for 7 days left (14 puffs).
  • Once the dose indicator reaches the end of the red scale, your Spiriva Respimat locks automatically – no more doses can be released. At this point, the clear base cannot be turned any further.
  • Three months after first use, the Spiriva Respimat should be discarded even if it has not been used.

Prepare for first use

  1. Remove clear base
  • Keep the cap closed.
  • Press the safety catch while firmly pulling off the clear base with your other hand.
  1. Insert cartridge
  • Insert the narrow end of the cartridge into the inhaler.
  • Place the inhaler on a firm surface and push down firmly until it snaps into place.
  1. Replace clear base
  • Put the clear base back into place until it clicks.
  1. Turn
  • Keep the cap closed.
  • Turn the clear base in the direction of the arrows on the label until it clicks (half a turn).
  1. Open
  • Open the cap until it snaps fully open.
  1. Press
  • Point the inhaler toward the ground
  • Press the dose-release button.
  • Close the cap.
  • Repeat steps 4-6 until a cloud is visible.
  • After a cloud is visible, repeat steps 4-6 three more times.

Daily use

TURN

  • Keep the cap closed.
  • TURN the clear base in the direction of the arrows on the label until it clicks (half a turn).

OPEN

  • OPEN the cap until it snaps fully open.

PRESS

  • Breathe out slowly and fully.
  • Close your lips around the mouthpiece without covering the air vents.
  • While taking a slow, deep breath through your mouth, PRESS the dose-release button and continue to breathe in.
  • Hold your breath for 10 seconds or for as long as comfortable.
  • Repeat Turn, Open, Press for a total of 2 puffs.

Answers to Common Questions

It is difficult to insert the cartridge deep enough

Did you accidentally turn the clear base before inserting the cartridge? Open the cap, press the dose-release button, then insert the cartridge.

Did you insert the cartridge with the wide end first? Insert the cartridge with the narrow end first.

Did you place the inhaler on a firm surface and push down firmly until the cartridge snaps into place? The cartridge should be pushed firmly against a firm surface to ensure that it has gone all the way in. The cartridge will not be flush with the inhaler, you will see the silver ring of the lower end of the cartridge.

I cannot press the dose-release button

Did you turn the clear base? If not, turn the clear base in a continuous movement until it clicks (half a turn).

Is the dose indicator on the Spiriva Respimat pointing to zero? The Spiriva Respimat inhaler is locked after 60 puffs (30 medicinal doses). Prepare and use your new Spiriva Respimat inhaler.

I cannot turn the clear base

Did you turn the clear base already?
If the clear base has already been turned, follow steps “OPEN” and “PRESS” under “Daily use” to get your medicine.

Is the dose indicator on the Spiriva Respimat pointing to zero? The Spiriva Respimat inhaler is locked after 60 puffs (30 medicinal doses). Prepare and use your new Spiriva Respimat inhaler.

The dose indicator on the Spiriva Respimat reaches zero too soon

Did you use Spiriva Respimat as indicated (two puffs/once daily)? Spiriva Respimat will last 30 days if used at two puffs once daily.

Did you turn the clear base before you inserted the cartridge? The dose indicator counts each turn of the clear base regardless whether a cartridge has been inserted or not.

Did you spray in the air often to check whether the Spiriva Respimat is working? Once you have prepared Spiriva Respimat, no test-spraying is required if used daily.

Did you insert the cartridge into a used Spiriva Respimat inhaler? Always insert a new cartridge into a NEW Spiriva Respimat inhaler.

My Spiriva Respimat sprays automatically

Was the cap open when you turned the clear base? Close the cap, then turn the clear base.

Did you press the dose-release button when turning the clear base? Close the cap, so the dose-release button is covered, then turn the clear base.

Did you stop when turning the clear base before it clicked? Turn the clear base in a continuous movement until it clicks (half a turn).

My Spiriva Respimat doesn’t spray

Did you insert a cartridge? If not, insert a cartridge.

Did you repeat Turn, Open, Press less than three times after inserting the cartridge? Repeat Turn, Open, Press three times after inserting the cartridge as shown in the steps 4 to 6 under “Prepare for first use”.

Is the dose indicator on the Spiriva Respimat pointing to 0? If the dose indicator points to 0, you have used up all your medication and the inhaler is locked.

Once your Spiriva Respimat is assembled, do not remove the clear base or the cartridge. Always insert a new cartridge into a NEW Spiriva Respimat inhaler.

Supplier

Spiriva Respimat inhaler is supplied in Australia by:

Boehringer Ingelheim Pty Limited
ABN 52 000 452 308
78 Waterloo Road
NORTH RYDE NSW 2113

Manufacturer

Spiriva Respimat inhaler is manufactured by:

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Straße 173
D-55216 Ingelheim am Rhein
Germany

BRAND INFORMATION

Brand name

Spiriva Respimat Solution for inhalation

Active ingredient

Tiotropium bromide

Schedule

S4

 

1 Name of Medicine

Tiotropium (as tiotropium bromide monohydrate).

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 sulfoxide, 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 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).

Chemical structure.


CAS number.

139404-48-1.

2 Qualitative and Quantitative Composition

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

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.

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 picomolar). 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 nonclinical 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 nanomolar 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 microgram 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 microgram) 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 microgram); 5,694 patients receiving Spiriva HandiHaler). The primary endpoints were time to first COPD exacerbation, time to all cause mortality and in a substudy (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 (see 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 (see 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 (see 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 (see 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 (see 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 nonchiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium bromide is available as solution for inhalation administered by the Respimat 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 gastrointestinal 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 multicompartmental 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 nonenzymatic 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 nonabsorbed 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 postdose 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 nonenzymatic 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 0.8 x (male mouse), 38 x (female mouse) and 16 x (rat) greater than the maximum recommended human daily dose of the drug, based on body surface area.

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.

4.3 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 nonsignificant 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 inhaler (see Respimat 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 coadministration 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 coadministration of tiotropium bromide with other anticholinergic medicines has not been studied. Therefore, the chronic coadministration 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 (750 x 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 750 x and 400 x 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.

4.8 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 postapproval 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.

4.2 Dose and Method of Administration

The recommended dosage of tiotropium using the Spiriva Respimat is 5 micrograms. This is administered as two puffs once daily at the same time each day (see Respimat inhaler Instructions for Use).
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 dosage 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 inhaler, at the same time each day (see Respimat inhaler Instructions for Use).

Special populations.

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

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.

4.9 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 microgram tiotropium in healthy volunteers. Additionally, no relevant adverse effects, beyond dry mouth, were observed following 7 day dosing of up to 141 microgram tiotropium in healthy volunteers. In a multiple dose study in patients with COPD, with a maximum daily dose of 36 microgram 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 microgram 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 microgram tiotropium solution for inhalation was given over 4-48 weeks.

7 Medicine Schedule (Poisons Standard)

S4.

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.

In-use shelf life.

Spiriva Respimat cartridges. The cartridge has an in-use shelf life of 3 months after insertion in the Respimat inhaler.

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

Each pack consists of one Respimat inhaler and one cartridge, delivering 60 metered puffs.

6.6 Special Precautions for Disposal

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

Summary Table of Changes