Consumer medicine information

Spiolto Respimat (with dose indicator)

Tiotropium; Olodaterol

BRAND INFORMATION

Brand name

Spiolto Respimat (with dose indicator)

Active ingredient

Tiotropium; Olodaterol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

SUMMARY CMI

Spiolto® 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 Spiolto Respimat?

Spiolto Respimat contains the active ingredients tiotropium (as bromide monohydrate) and olodaterol (as hydrochloride). Spiolto Respimat is used for the treatment of Chronic Obstructive Pulmonary Disease (COPD). COPD is a serious lung condition that can cause difficulty in breathing and constant coughing.

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

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

Do not use if you have ever had an allergic reaction to tiotropium, olodaterol, 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 Spiolto Respimat? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Spiolto 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 Spiolto Respimat?

  • Spiolto Respimat is for inhalation use only.
  • Read the Instructions for Use and follow the diagrams that show you how to use the Spiolto Respimat re-usable inhaler.
  • Take 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 Spiolto Respimat? in the full CMI.

5. What should I know while using Spiolto Respimat?

Things you should do
  • Stop using Spiolto Respimat and tell your doctor immediately if you get sudden tightness of the chest, coughing, wheezing or breathlessness immediately after using Spiolto Respimat.
  • Remind any doctor, dentist or pharmacist you visit that you are using Spiolto Respimat.
Things you should not do
  • Do not use Spiolto Respimat to relieve an acute attack of breathlessness or wheezing.
  • Do not stop using your medicine or lower the dosage without checking with your doctor.
Driving or using machines
  • Spiolto 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 Spiolto Respimat affects you.
Looking after your medicine
  • Keep Spiolto Respimat in a cool dry place where the temperature stays below 30°C. Do not freeze.
  • Replace the cartridge not later than three months after insertion.
  • The recommended use is 6 cartridges per Respimat re-usable inhaler.

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

6. Are there any side effects?

Side effects that require urgent medical attention include allergic reaction, chest pain (angina pectoris/heart attack), severe pain in the stomach with bloating, gut cramps and vomiting and signs of metabolic acidosis (increased rate of breathing, faster heartbeat, headache, confusion, weakness, tiredness, nausea, vomiting and loss of appetite).

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

Spiolto® Respimat®

Active ingredients: tiotropium (as bromide monohydrate) / olodaterol (as hydrochloride)

Consumer Medicine Information (CMI)

This leaflet provides important information about using Spiolto 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 Spiolto Respimat.

Where to find information in this leaflet:

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

1. Why am I using Spiolto Respimat?

Spiolto Respimat contains the active ingredients tiotropium (as bromide monohydrate) and olodaterol (as hydrochloride). Tiotropium belongs to a group of medicines called anticholinergics. Olodaterol belongs to a group of medicines called long-acting bronchodilators. These medicines are used to relax the breathing tubes or air passages that carry air to and from the lungs and to keep the air passages in the lungs open and make breathing easier.

Spiolto Respimat is used for the treatment of 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. Symptoms of COPD include shortness of breath, cough, chest discomfort and coughing up phlegm.

Regular use of Spiolto Respimat can also help when you have ongoing shortness of breath related to your disease, and will help minimise the effects of the disease on your everyday life.

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

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

Warnings

Do not use Spiolto Respimat to relieve an acute attack of breathlessness or wheezing. You will need a different type of medicine known as a 'reliever' for this. Spiolto Respimat should only be used for maintenance treatment of your COPD.

Do not use Spiolto Respimat if you are allergic to:

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

Do not use Spiolto Respimat to treat asthma. Safety and effectiveness in the treatment of asthma has not been established.

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

Check with your doctor if:

  • You have or have had any of the following medical conditions:
    - asthma (you should not use Spiolto Respimat to treat your asthma)
    - acute worsening of your breathing problems
    - heart problems
    - high blood pressure
    - seizures
    - overactive thyroid gland (thyrotoxicosis)
    - high pressure in the eye (glaucoma)
    - kidney or liver problems
    - problems with passing urine
    - problems with your prostate gland
    - diabetes
    - severe liver problems

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

Pregnancy and breastfeeding

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

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

Children and adolescents

Do not give this medicine to a child or adolescent under the age of 18 years.

Safety and effectiveness in children younger than 18 years have not been established.

Eyes

Do not allow the mist to enter your eyes. Should this occur, immediately flush your eyes with cold tap water for several minutes, stop using Spiolto Respimat 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 Spiolto Respimat re-usable inhaler can only be used with Spiolto Respimat cartridges.

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

Tell your doctor or pharmacist if you are taking any other medicines/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 Spiolto Respimat may interfere with each other. These include:

  • Similar medicines used to treat your breathing problems, including other anticholinergic medicines such as ipratropium
  • Medicines that can lower the amount of potassium in your blood. These include medicines used to treat breathing problems such as theophylline, steroids such as prednisolone and diuretics (water tablets)
  • Medicines used to treat high blood pressure, heart conditions, glaucoma and migraine such as propranolol (beta-blockers)
  • Medicines used for glaucoma, including eye drops such as timolol
  • Medicines used to treat depression and other mental disorders such as tricyclic antidepressants (amitriptyline, nortriptyline, clomipramine, dothiepin, doxepin and imipramine or Monoamine oxidase (MAO) inhibitors (like selegiline, moclobemide, phenelzine and tranylcypromine).

You may need to take 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 Spiolto Respimat.

4. How do I use Spiolto Respimat?

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. Two puffs are equal to one dose.

Each dose of Spiolto Respimat will keep your air passages open for 24 hours.

Follow the instructions provided and use Spiolto Respimat until your doctor tells you to stop.

When to use Spiolto Respimat

Spiolto Respimat should be used at about the same time each day.

How to use Spiolto Respimat

  • Spiolto Respimat is for inhalation use only. The solution for inhalation is contained in the Spiolto Respimat cartridge and inhaled using the Spiolto Respimat re-usable inhaler supplied with the medicine.
  • Make sure that you know how to use your Spiolto Respimat re-usable inhaler properly.
  • Read the Instructions for Use and follow the diagrams that show you how to use the Spiolto Respimat re-usable inhaler.
  • The Instructions for Use are also available via the following hyperlink: medsinfo.com.au/media/byispiri

Use the Spiolto Respimat re-usable inhaler supplied in the pack to breathe in the solution containing the medicine from the Spiolto Respimat cartridge.

Insert the Spiolto Respimat cartridge into the Spiolto Respimat re-usable inhaler to prepare the inhaler for use.

The Spiolto 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 Spiolto Respimat re-usable inhaler, ask your doctor or pharmacist for help.

If you forget to use Spiolto Respimat

If you forget to use your Spiolto 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 use too much Spiolto Respimat

If you think that you have used too much Spiolto 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:

  • chest pain
  • high or low blood pressure, dizziness, light-headedness
  • blurred vision
  • changes in the heart rate (fast, slow or irregular), palpitations
  • nervousness or feeling anxious
  • inability to sleep
  • headache
  • shaking or tremors
  • dry mouth
  • muscle cramps or spasm
  • muscle weakness
  • feeling sick, also called nausea
  • stomach pain
  • constipation
  • fatigue
  • generally feeling unwell
  • passing large amounts of urine, excessive thirst and having a dry mouth and skin
  • difficulty passing urine
  • increased rate of breathing.

5. What should I know while using Spiolto Respimat?

Things you should do

  • Stop using Spiolto Respimat and tell your doctor immediately if you get sudden tightness of the chest, coughing, wheezing or breathlessness immediately after using the Spiolto Respimat. These may be signs of a condition called bronchospasm.
  • 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 Spiolto Respimat, especially if you are about to start any new medicine or if you are going to have surgery.
  • If you are a smoker, you should stop smoking. Your doctor or pharmacist can advise you on the steps to take to quit smoking.

Tell your doctor immediately if:

  • You become pregnant while using Spiolto Respimat.

Things you should not do

  • Do not use Spiolto Respimat to relieve an acute attack of breathlessness or wheezing. If you become wheezy or tight in the chest before your next dose of Spiolto Respimat is due, use a 'reliever puffer' in the usual way. Spiolto Respimat should only be used for maintenance treatment of your COPD.
  • Do not use Spiolto 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 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.

Driving or using machines

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

Spiolto Respimat 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 Respimat re-usable inhaler Instructions for Use on how to clean and take care of your Spiolto 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 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 Respimat re-usable inhaler.
  • Keep Spiolto Respimat in a cool dry place where the temperature stays below 30°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 list of side effects. You may not experience any of them.

Less serious side effects

Less serious side effectsWhat to do
Brain and nerves:
  • headache
  • dizziness
  • tiredness (fatigue)
  • shaking
  • nervousness
  • generally feeling unwell
  • trouble sleeping.
Nose and sinus:
  • runny nose or nose bleeds
  • sinusitis, a feeling of tension or fullness in the nose, cheeks and behind your eyes, sometimes with a throbbing ache, fever, stuffy nose and loss of the sense of smell.
Mouth, throat and airways:
  • dry or sore mouth or throat and discomfort when swallowing; swollen, red, sore tongue
  • Inflammation of the gums (gingivitis) or tooth decay
  • sore, creamy-yellow, raised patches in the mouth or throat (oral thrush)
  • hoarse voice
  • flu-like symptoms, such as high temperature, sore throat, runny nose, cough and chills
  • shortness of breath, cough, or chest infections.
Gut and digestion:
  • a burning sensation in the chest rising up to the throat, also known as heartburn
  • feeling sick (nausea)
  • a change in bowel movements, e.g. constipation.
Metabolism and Nutrition:
  • dehydration.
Musculoskeletal and Connective tissue:
  • back or joint pain, joint swelling
  • muscle spasm.
Skin:
  • rash or dry skin
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
  • worsening of breathing problems (induced by the inhalation process). Inhaled medicines such as Spiolto Respimat may cause tightness of the chest, coughing, wheezing or breathlessness immediately after inhalation
  • increased rate of breathing
  • difficulty swallowing.
Heart:
  • changes in the rhythm or rate of heartbeat (fast, slow or irregular)
  • feeling of fluttering, racing or skipping heart beats (palpitations)
  • increase or decrease in blood pressure.
Bladder:
  • difficulty passing urine
  • signs of a urinary tract infection such as:
    - 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.
Signs of low potassium levels in the blood:
  • muscle spasm
  • muscle weakness
  • abnormal heart rhythm.
Signs of high blood sugar levels:
  • passing large amounts of urine
  • excessive thirst
  • dry mouth and skin.
Skin
  • skin infection or skin ulcer.
Speak with 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 swallowing or breathing
  • swelling of other parts of the body
  • rash, itching or hives on the skin.
Heart:
  • chest pain (angina pectoris/heart attack).
Gut and digestion:
  • severe pain in the stomach with bloating, gut cramps and vomiting.
Signs of metabolic acidosis:
  • increased rate of breathing
  • faster heartbeat
  • headache or confusion
  • weakness
  • tiredness
  • nausea and vomiting
  • loss of appetite.
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 Spiolto Respimat contains

Active ingredients
(main ingredients)		Per puff:
  • 2.5 micrograms tiotropium (as bromide monohydrate), and
  • 2.5 micrograms olodaterol (as hydrochloride).
Other ingredients
(inactive ingredients)
  • benzalkonium chloride
  • disodium edetate
  • hydrochloric acid
  • purified water.

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

What Spiolto Respimat looks like

Spiolto Respimat is available as a solution for inhalation contained in the cartridge. The Spiolto Respimat re-usable inhaler (with a light-green coloured cap) enables you to inhale the medicine from the cartridge. (AUST R 326008).

Single pack: 1 Spiolto Respimat reusable inhaler and 1 Spiolto Respimat cartridge, providing 60 puffs (30 doses).

Triple pack: 1 Spiolto Respimat reusable inhaler and 3 Spiolto Respimat cartridges, providing 60 puffs (30 doses) each. *

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

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

*Not all pack sizes may be marketed.

Who distributes Spiolto Respimat

Spiolto Respimat is distributed in Australia by:

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

This leaflet was revised in February 2024.

® Spiolto and Respimat are registered trademarks of Boehringer Ingelheim.

© Boehringer Ingelheim Pty Limited 2024

Published by MIMS May 2024

BRAND INFORMATION

Brand name

Spiolto Respimat (with dose indicator)

Active ingredient

Tiotropium; Olodaterol

Schedule

S4

 

1 Name of Medicine

Tiotropium (as bromide monohydrate) and olodaterol (as hydrochloride).

2 Qualitative and Quantitative Composition

Spiolto Respimat is a soft mist inhaler delivering tiotropium + olodaterol solution for inhalation. The Spiolto Respimat cartridge containing the solution for inhalation is only for use with the Spiolto Respimat re-usable inhaler. The delivered dose is 2.5 microgram tiotropium and 2.5 microgram olodaterol per puff (2 puffs comprise one medicinal dose) and is equivalent to 3.124 micrograms tiotropium bromide monohydrate and 2.7 micrograms olodaterol hydrochloride. Two puffs equal one dose of 5 micrograms/5 micrograms. The delivered dose is the dose which is available for the patient after passing the mouthpiece.

Excipients with known effect.

Spiolto 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

Spiolto Respimat solution for inhalation is a clear, colourless solution contained in a plastic container crimped into an aluminium cylinder (cartridge) with a dose counter, for use with the Spiolto Respimat re-usable inhaler. The Spiolto Respimat re-usable inhaler has a light-green coloured cap. The Spiolto Respimat cartridge is only intended for use with the Spiolto Respimat re-usable inhaler.

4 Clinical Particulars

4.1 Therapeutic Indications

Spiolto Respimat is indicated as a once-daily maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).

4.2 Dose and Method of Administration

Spiolto Respimat is for oral inhalation only.

Adults.

The recommended dose for adults is 5 microgram tiotropium and 5 microgram olodaterol given as two puffs from the Spiolto Respimat inhaler once daily, at the same time of the day (see Section 4.2 Dose and Method of Administration, Instructions for use and handling).

Children.

COPD does not normally occur in children. The safety and effectiveness of Spiolto Respimat in the paediatric population have not been established.

Elderly.

Elderly patients can use Spiolto Respimat at the recommended dose.

Patients with hepatic impairment.

Spiolto Respimat contains olodaterol, which is predominantly metabolised in the liver.
Patients with mild and moderate hepatic impairment can use Spiolto Respimat at the recommended dose.
There are no data available for use of Spiolto Respimat in patients with severe hepatic impairment.

Patients with renal impairment.

Renally impaired patients can use Spiolto Respimat at the recommended dose.
Spiolto Respimat contains tiotropium, which is a predominantly renally excreted drug. Therefore, Spiolto Respimat use should be monitored closely in patients with moderate to severe renal impairment.

Instructions for use and handling.

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

4.3 Contraindications

Spiolto Respimat is contraindicated in patients with hypersensitivity to tiotropium or olodaterol or to any of the excipients.
Spiolto Respimat is also contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, e.g. ipratropium or oxitropium.

4.4 Special Warnings and Precautions for Use

General warnings.

Spiolto Respimat should not be used more frequently than once daily.
Spiolto Respimat contains 0.0011 mg benzalkonium chloride in each actuation.
Benzalkonium chloride may cause wheezing and breathing difficulties. Patients with asthma are at an increased risk for these adverse events.

Asthma.

Spiolto Respimat should not be used in the treatment of asthma as the efficacy and safety have not been studied in this indication.
The long-term efficacy and safety of olodaterol in the treatment of asthma have not been studied. LABAs may increase the risk of asthma-related hospitalisations and death. Data from a large placebo-controlled study that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABAs, including olodaterol, one of the active ingredients in Spiolto Respimat.

Acute bronchospasm.

Spiolto Respimat is not indicated for the treatment of acute episodes of bronchospasm, i.e. as rescue therapy.

Deterioration of disease and acute episodes.

Spiolto Respimat should not be initiated in patients with acutely deteriorating COPD. In this case, the patient's COPD management plan should direct the patient to seek medical advice immediately, and a re-evaluation of the patient and the COPD treatment regimen should be undertaken. Increasing the daily dosage of Spiolto Respimat beyond the recommended dose is not appropriate.

Hypersensitivity.

As with all medications, immediate hypersensitivity reactions may occur after administration of Spiolto Respimat.

Paradoxical bronchospasm.

As with other inhaled medicines Spiolto Respimat may result in paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs Spiolto Respimat should be discontinued immediately and alternative therapy substituted.

Narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction.

Consistent with the anticholinergic activity of tiotropium, Spiolto 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, tiotropium was associated with a non-significant increase in the risk of urinary retention, and a significant increase in the risk of micturition difficulties.

Eye symptoms.

Patients must be instructed in the correct administration of Spiolto Respimat. 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.

Systemic effects.

Spiolto Respimat contains a long acting beta2-adrenergic agonist. LABAs should be administered with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, hypertrophic obstructive cardiomyopathy and hypertension; in patients with convulsive disorders or thyrotoxicosis, in patients with known or suspected prolongation of the QT interval; and in patients who are unusually responsive to sympathomimetic amines.

Cardiovascular effects.

Like other beta2-adrenergic agonists, olodaterol may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. In case such effects occur, treatment may need to be discontinued. In addition, beta-adrenergic agonists have been reported to produce ECG changes, such as flattening of the T wave and ST segment depression, although the clinical significance of these observations is unknown.
Patients with a history of myocardial infarction during the previous year, unstable or life-threatening cardiac arrhythmia, hospitalised for heart failure during the previous year or with a diagnosis of paroxysmal tachycardia (> 100 beats per minute) were excluded from the clinical trials. Therefore the experience in these patient groups is limited. Spiolto Respimat should be used with caution in these patient groups.

Hypokalaemia.

Beta2-adrenergic agonists may produce significant hypokalaemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), which may increase the susceptibility to cardiac arrhythmias.

Hyperglycaemia.

Inhalation of high doses of beta2-adrenergic agonists may produce increases in plasma glucose.

Use in hepatic impairment.

Based on pharmacokinetic data of the tiotropium and olodaterol monotherapies, patients with mild and moderate hepatic impairment can use Spiolto Respimat at the recommended dose.
There are no data available for use of Spiolto Respimat in patients with severe hepatic impairment. These patients should be closely monitored.

Use in renal impairment.

Because tiotropium is a predominantly renally excreted drug, Spiolto Respimat use should be monitored closely in patients with moderate to severe renal impairment (creatinine clearance of ≤ 50 mL/min) (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

Elderly patients can use Spiolto Respimat at the recommended dose.

Paediatric use.

COPD does not normally occur in children. The safety and effectiveness of Spiolto Respimat in the paediatric population have not been established.

Effects on laboratory tests.

No data available.

Other.

Spiolto Respimat should not be used in conjunction with any other medication containing LABAs or LAMAs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients who have been taking inhaled, short acting beta2-adrenergic agonists on a regular basis (e.g. four times a day) should be instructed to use them only for symptomatic relief of acute respiratory symptoms.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Tiotropium.

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, methylxanthines, oral and inhaled steroids, without clinical evidence of drug interactions.
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 Spiolto Respimat is not recommended.

Olodaterol.

In vitro studies indicated pharmacokinetic drug interactions involving CYP450 enzymes are not expected. Inhibitors of P-glycoprotein, OAT1, OAT3 or OCT1 may alter the systemic exposure to or disposition of olodaterol. Olodaterol was not an inhibitor of these transporters at clinically-relevant concentrations.

Adrenergic agents.

Concomitant administration of other adrenergic agents may potentiate the undesirable effects of Spiolto Respimat.

Xanthine derivatives, steroids or diuretics.

Concomitant treatment with xanthine derivatives, steroids, or non-potassium sparing diuretics may potentiate any hypokalaemic effect of adrenergic agonists (see Section 4.4 Special Warnings and Precautions for Use).

Beta-blockers.

Beta-adrenergic blockers may weaken or antagonise the effect of olodaterol. Cardioselective beta-blockers could be considered, although they should be administered with caution.

MAO inhibitors, tricyclic antidepressants, QTc prolonging drugs.

Monoamine oxidase inhibitors, or tricyclic antidepressants or other drugs known to prolong the QTc interval may potentiate the action of Spiolto Respimat on the cardiovascular system.

Pharmacokinetic drug-drug interactions.

In a drug interaction study with olodaterol using the strong dual CYP and P-gp inhibitor ketoconazole, a 1.7-fold increase of systemic exposure was observed (see Section 5.2 Pharmacokinetic Properties). No safety concerns were identified in clinical studies of up to one year with olodaterol at doses up to twice the recommended therapeutic dose. No dose adjustment of Spiolto Respimat is necessary.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Clinical data on fertility are not available for tiotropium and olodaterol or the combination of both components. Nonclinical studies performed with the individual components tiotropium and olodaterol showed no adverse effect on fertility.
No reproduction toxicity studies for the combination were performed.

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).

Olodaterol.

Decreased epididymal and testicular weights were seen in rats at inhalational doses greater than or equal to 55 microgram/kg/day; however there was no effect on sperm count, concentration or motility. No impairment of male or female fertility or early embryonic development was seen in the rat at inhalational doses up to approximately 3,000 microgram/kg/day (plasma AUC more than 2,000 times the anticipated AUC in adults from a 5 microgram dose basis).
(Category B3)
There is a limited amount of data from the use of tiotropium in pregnant women. For olodaterol no clinical data on exposed pregnancies is available.

Tiotropium.

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.

Olodaterol.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant exposures.
Olodaterol and/or its metabolites crossed the placenta in rats. In the rat, no teratogenic effects occurred after inhalation of doses up to 1,054 microgram/kg/day (plasma AUC approximately 3,000 times the anticipated AUC in adults). In pregnant rabbits, the administered inhalational dose of 2,489 microgram/kg/day olodaterol exhibited foetal toxicity characteristic of beta-adrenoceptor stimulation; these included patchy ossifications, short/bent bones, partially open eye, cleft palate, and cardiovascular abnormalities. No significant effects occurred at an inhalational dose of 974 microgram/kg/day (approximately 1,300 times the anticipated AUC in adults).
As a precautionary measure, it is preferable to avoid the use of Spiolto Respimat during pregnancy.
The inhibitory effect of beta-adrenergic agonists, like olodaterol a component of Spiolto Respimat, on uterine contraction should be taken into account.
 Clinical data from lactating women exposed to tiotropium and/or olodaterol are not available.
In preclinical studies for both tiotropium and olodaterol the substances and/or its metabolites have been detected in the milk of lactating rats, but it is not known whether tiotropium and/or olodaterol pass into human breast milk.
Therefore, Spiolto 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.
However, patients should be advised that dizziness and blurred vision have been reported with the use of Spiolto Respimat. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience such symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.
The clinical development program of Spiolto Respimat encompassed more than 19,000 patients with COPD, of which more than 5,900 COPD patients received a dose of 5 microgram tiotropium and 5 microgram olodaterol.
Side effects of Spiolto Respimat were primarily identified from data obtained in 2 active-controlled, parallel-group, long-term treatment (52 weeks) clinical trials in COPD patients comparing Spiolto Respimat with tiotropium and olodaterol. Additionally, a third active-controlled, parallel-group, long-term treatment (52 weeks) clinical trial in COPD patients comparing Spiolto Respimat with tiotropium was conducted (Trial 9).
In the two pivotal trials (Trials 1 and 2) the overall incidence of adverse events in patients treated with Spiolto Respimat was comparable to patients treated with the mono compound olodaterol at a dose of 5 microgram (74% and 76.6%, respectively). In the pooled analysis of all three long-term clinical trials (Trial 1, Trial 2 and Trial 9) the overall incidence of adverse events in patients treated with Spiolto Respimat was comparable to patients treated with the mono components tiotropium at a dose of 5 microgram (74.1% and 74.3% respectively). All undesirable effects previously reported with one of the individual components are considered undesirable effects with Spiolto Respimat and are included in the adverse reactions listed below. In Trial 9, no new side effects were identified contributing more than 3,900 COPD patients treated with Spiolto Respimat; furthermore the safety profile was consistent with that documented in the pivotal trials.
Table 1 shows all adverse events from Trials 1 and 2 that occurred with an incidence of > 2% with Spiolto Respimat treatment group and a higher incidence rate than the active comparator groups listed. The rates are derived from all reported adverse events of that type, regardless if considered drug-related or not by the clinical investigator.
Table 2 shows all adverse events from Trial 9 that occurred with an incidence of > 2% with Spiolto Respimat treatment group and a higher incidence rate than the active comparator group listed. The rates are derived from all reported adverse events of that type, regardless if considered drug-related or not by the clinical investigator.
Adverse reactions reported in all clinical trials with Spiolto Respimat with a frequency of less than 2% are shown in Table 3 according to system organ class. These also include all adverse reactions previously reported with one of the individual components.
Frequency is defined using the following convention: Very common ≥ 1/10; Common ≥ 1/100, < 1/10; Uncommon ≥ 1/1,000, < 1/100; Rare ≥ 1/10,000, < 1/1,000; Very rare < 1/10,000; Not known cannot be estimated from the available data.
Many of the listed adverse effects can be assigned to either the anticholinergic properties of tiotropium or to the β-adrenergic properties of olodaterol, the components of Spiolto Respimat.
In addition the occurrence of other undesirable effects related to the beta-adrenergic agonist class, which are not listed above, should be taken into consideration, such as arrhythmia, myocardial ischaemia, angina pectoris, hypotension, tremor, headache, nervousness, nausea, muscle spasms, fatigue, malaise, hypokalaemia, hyperglycaemia, and metabolic acidosis.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

Symptoms.

High doses of tiotropium may lead to anticholinergic signs and symptoms.
No relevant adverse events, beyond dry mouth/throat and dry nasal mucosa in a dose-dependent [10-40 microgram daily] incidence, were observed following 14 day dosing of up to 40 microgram tiotropium inhalation solution 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 COPD patients when a daily dose of 10 microgram tiotropium inhalation solution was given over 4-48 weeks.
An overdose of olodaterol is likely to lead to exaggerated effects typical of beta2-adrenergic agonists, i.e. myocardial ischemia, hypertension or hypotension, tachycardia, arrhythmias, palpitation, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, muscle spasms, nausea, fatigue, malaise, hypokalaemia, hyperglycaemia and metabolic acidosis.

Treatment.

Treatment with Spiolto Respimat should be discontinued. Supportive and symptomatic treatment is indicated. Serious cases should be hospitalised. Use of cardioselective beta-blockers may be considered, but only subject to extreme caution since the use of beta-adrenergic blocker medication may provoke bronchospasm.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with anticholinergics.
ATC code: RO3AL06.

Mechanism of action.

Spiolto Respimat. Tiotropium, a long acting muscarinic antagonist and olodaterol a long acting beta2-adrenergic are administered together in the Spiolto Respimat soft mist inhaler. These two active ingredients are intended to provide additive bronchodilation due to their different mode of action and different locations of the target receptors in the lungs.

Tiotropium.

Tiotropium is a long-acting, muscarinic receptor antagonist (LAMA) (anticholinergic). It has similar affinity to the muscarinic receptor subtypes M1 to M5 (KD 5-41 picoM). 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 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).
The bronchodilation following inhalation of tiotropium is primarily a local effect on the airways, not a systemic one.

Olodaterol.

Functional in vitro assays indicate greater activity of olodaterol at human beta2-adrenoceptors than beta1- or beta3-adrenoceptors. The compound exerts its pharmacological effects by binding and activation of beta2-adrenoceptors after topical administration by inhalation.
Activation of these receptors in the airways results in a stimulation of intracellular adenyl cyclase, an enzyme that mediates the synthesis of cyclic-3',5' adenosine monophosphate (cAMP). Elevated levels of cAMP induce bronchodilation by relaxation of airway smooth muscle cells.
Olodaterol has the pre-clinical profile of a long-acting selective beta2-adrenoceptor agonist (LABA) with a fast onset of action and duration of action of at least 24 hours.
Beta-adrenoceptors are divided into three subtypes, beta1-adrenoceptors predominantly expressed on cardiac muscle, beta2-adrenoceptors predominantly expressed on airway smooth muscle and beta3-adrenoceptors predominantly expressed on adipose tissue. Beta2-agonists cause bronchodilation. Although the beta2-adrenoceptor is the predominant adrenergic receptor in the airway smooth muscle it is also present on the surface of a variety of other cells, including lung epithelial and endothelial cells and in the heart. The precise function of beta2-receptors in the heart is not known, but their presence raises the possibility that even highly selective beta2-adrenergic agonists may have cardiac effects.
Effects on cardiac electrophysiology.

Tiotropium.

In a dedicated QT study involving 53 healthy volunteers, Spiriva 18 microgram and 54 microgram (i.e. three times the therapeutic dose) over 12 days did not significantly prolong QT intervals of the electrocardiogram (ECG).

Olodaterol.

The effect of olodaterol on the QT/QTc interval of the ECG was investigated in 24 healthy male and female volunteers in a double-blind, randomised, placebo- and active (moxifloxacin) controlled study. Olodaterol at single doses of 10, 20, 30 and 50 microgram, demonstrated that compared with placebo, the mean changes from baseline in QT interval over 20 minutes to 2 hours after dosing increased dose-dependently from 1.6 (10 microgram olodaterol) to 6.5 ms (50 microgram olodaterol), with the upper limit of the two-sided 90% confidence intervals being less than 10 ms at all dose levels.
The effect of 5 microgram and 10 microgram olodaterol on heart rate and rhythm was assessed using continuous 24-hour ECG recording (Holter monitoring) in a subset of 772 patients in the 48-week, placebo-controlled Phase 3 Trials. There were no dose or time related trends or patterns observed for the magnitudes of mean changes in heart rate or premature beats. Shifts from baseline to the end of treatment in premature beats did not indicate meaningful differences between olodaterol 5 microgram, 10 microgram and placebo.

Spiolto Respimat.

In two 52-week randomised, double-blind trials using Spiolto Respimat that enrolled 5,162 patients with COPD, ECG assessments were performed post-dose on days 1, 85, 169, and 365. In a pooled analysis the number of subjects with changes from baseline-corrected QT interval of > 30 ms using both the Bazett (QTcB) and Fredericia (QTcF), corrections of QT for heart rate ranged from 4.9-6.4% (QTcB) and 1.3-4.7% (QTcF) for the Spiolto Respimat group compared to 5.0-6.0% (QTcB) and 1.3-4.4% (QTcF) for olodaterol 5 microgram and 5.3-6.5% (QTcB) and 2.1-4.6% (QTcF) for tiotropium 5 microgram across the assessments conducted.

Clinical trials.

The Phase III clinical development program for Spiolto Respimat included three randomised, double-blind trials:
(i) two replicate, 52 week parallel group trials comparing Spiolto Respimat with tiotropium 5 microgram and olodaterol 5 microgram (1,029 received Spiolto Respimat) [Trials 1 and 2];
(ii) one 6 week cross-over trial comparing Spiolto Respimat with tiotropium 5 microgram and olodaterol 5 microgram and placebo (139 received Spiolto Respimat) [Trial 3].
In these trials, the comparator products, tiotropium 5 microgram, olodaterol 5 microgram and placebo, were administered via the Respimat inhaler.
All studies included lung function measurements (forced expiratory volume in one second, FEV1). In the 52 week studies, lung function was measured up to 3 hours post-dose (12 hours post-dose in a subset of patients) and at 23-24 hours post-dose; the primary lung function efficacy endpoints were change from pre-treatment baseline (response) in FEV1 AUC0-3h and trough FEV1 after 24 weeks. In the 6 week study, lung function was measured up to 12 hours post-dose and at 22-24 hours post-dose; the primary efficacy endpoint was FEV1 AUC0-24h response after 6 weeks. The 52 week trials also included the St. George's Respiratory Questionnaire (SGRQ) as a primary endpoint as a measure of health-related quality of life and the Mahler Transition Dyspnoea Index (TDI) as a key secondary endpoint as a measure of dyspnoea.
Patients enrolled into the Phase III program were 40 years of age or older with a clinical diagnosis of COPD, had a smoking history of more than 10 pack years and had moderate to very severe pulmonary impairment (post-bronchodilator FEV1 less than 80% predicted normal (GOLD Stage 2-4); post-bronchodilator FEV1 to FVC ratio of less than 70%).

Patient characteristics.

The majority of the 5,162 patients recruited in the global, 52 week trials [Trials 1 and 2] were male (73%), white (71%) or Asian (25%), with a mean age of 64.0 years. Mean post-bronchodilator FEV1 was 1.37 L (GOLD 2 (50%), GOLD 3 (39%), and GOLD 4 (11%)). Mean β2-agonist responsiveness was 16.6% of baseline (0.171 L). Pulmonary medications allowed as concomitant therapy included inhaled steroids (47%) and xanthines (10%).
The 6 week trial [Trial 3] was conducted in Europe and North America. The majority of the 219 recruited patients were male (59%) and white (99%), with a mean age of 61.1 years. Mean post-bronchodilator FEV1 was 1.55 L (GOLD 2 (64%), GOLD 3 (34%), GOLD 4 (2%)). Mean β2-agonist responsiveness was 15.9% of baseline (0.193 L). Pulmonary medications allowed as concomitant therapy included inhaled steroids (41%) and xanthines (4%).

Lung function.

In the 52 week trials, Spiolto Respimat, administered once daily in the morning, provided clear improvement in lung function within 5 minutes after the first dose compared to tiotropium 5 microgram (mean increase in FEV1 of 0.137 L for Spiolto Respimat vs. 0.058 L for tiotropium 5 microgram [p < 0.0001] and 0.125 L for olodaterol 5 microgram [p=0.16]). In both studies, significant improvements were observed in FEV1 AUC0-3h response and trough FEV1 response after 24 weeks (lung function primary endpoints) for Spiolto Respimat compared to tiotropium 5 microgram and olodaterol 5 microgram (Table 4).
The increased bronchodilator effects of Spiolto Respimat compared to tiotropium 5 microgram and olodaterol 5 microgram were maintained throughout the 52 week treatment period. Spiolto Respimat also improved morning and evening PEFR (peak expiratory flow rate) compared to tiotropium 5 microgram and olodaterol 5 microgram as measured by patient's daily recordings.
In the subset of patients who completed extended lung function measurements up to 12 hours post-dose, Spiolto Respimat showed a significantly greater FEV1 response compared to tiotropium 5 microgram and olodaterol 5 microgram over the full 24 hour dosing interval (Figure 1, Table 5).
In the 6 week trial, Spiolto Respimat showed a significantly greater FEV1 response compared to tiotropium 5 microgram, olodaterol 5 microgram and placebo over the full 24 hour dosing interval (Figure 2, Table 6).

Dyspnoea.

After 24 weeks (Trials 1 and 2), Spiolto Respimat significantly improved mean TDI focal score compared to tiotropium 5 microgram and olodaterol 5 microgram (Table 7). More patients treated with Spiolto Respimat had a clinically meaningful improvement in TDI focal score (MCID, defined as a value of at least 1 unit) compared to tiotropium 5 microgram (54.9% vs. 50.6%, p=0.0546) and olodaterol 5 microgram (54.9% vs. 48.2%, p=0.0026).

Rescue medication use.

Patients treated with Spiolto Respimat used less daytime and night-time rescue salbutamol compared to patients treated with tiotropium 5 microgram and olodaterol 5 microgram (Trials 1 and 2).

Exacerbations.

Tiotropium 5 microgram has previously demonstrated a statistically significant reduction in risk of a COPD exacerbation compared to placebo. COPD exacerbations was included as an additional endpoint in the 52 week pivotal trials [Trials 1 and 2]. In the combined dataset, the proportion of patients experiencing a moderate/severe COPD exacerbation was 27.7% for Spiolto Respimat, 28.8% for tiotropium 5 microgram and 31.9% for olodaterol 5 microgram.
In a one-year, randomised, double-blind, active-controlled parallel group clinical trial (Trial 9) Spiolto Respimat was compared with tiotropium 5 microgram on COPD exacerbations. All respiratory medications except anticholinergics, long-acting beta-agonists and combinations thereof were allowed as concomitant treatment, i.e. rapidly acting beta-agonists, inhaled corticosteroids and xanthines. The primary endpoint was the annualised rate of moderate to severe COPD exacerbations (3939 patients received Spiolto Respimat and 3941 patients received tiotropium 5 microgram).
The majority of patients were male (71.4%) and Caucasian (79.3%). The mean age was 66.4 years, mean post-bronchodilator FEV1 was 1.187 L (SD 0.381), and 29.4% of patients had a history of clinically important cardiovascular disease.
Exacerbations of COPD were defined as "a complex of lower respiratory events/ symptoms (increase or new onset) related to the underlying COPD, with duration of three days or more, requiring a prescription of antibiotics and/or systemic steroids and/or hospitalisation".
Spiolto Respimat treatment resulted in an additional 7% reduction in the annualised rate of moderate to severe COPD exacerbations in comparison to tiotropium 5 microgram (rate ratio (RR) 0.93, 99% Confidence Interval (CI), 0.85-1.02, p=0.0498). The study was designed to reach a significance level of 1%. A post hoc analysis using a multiple covariate adjustment model, as done in other exacerbation studies, resulted in an additional 11% reduction in the annualised rate of moderate to severe COPD exacerbation in comparison to tiotropium 5 microgram (RR 0.89, 95% CI, 0.84-0.96, nominal p-value < 0.01).
There was no significant difference in the risk of all-cause mortality between Spiolto Respimat and tiotropium 5 microgram. During the planned study period (381 days), 107 deaths were observed for Spiolto Respimat compared with 121 for tiotropium 5 microgram (HR 0.88, 95% CI, 0.68, 1.15, p=0.3485).
The analysis of the additional exacerbation trial (Trial 9) is displayed in Table 8.

Health-related quality of life.

After 24 weeks (Trials 1 and 2), Spiolto Respimat significantly improved mean SGRQ total score compared to tiotropium 5 microgram and olodaterol 5 microgram (Table 9); improvements were seen in all SGRQ domains. More patients treated with Spiolto Respimat had a clinically meaningful improvement in SGRQ total score (MCID, defined as a decrease of at least 4 units from baseline) compared to tiotropium 5 microgram (57.5% vs. 48.7%, p=0.0001) and olodaterol 5 microgram (57.5% vs. 44.8%, p < 0.0001).
In two additional 12 week (Trials 7 and 8), placebo-controlled clinical trials, SGRQ total score at 12 weeks was also included as primary endpoint as a measure of health-related quality of life.
In the 12 week trials, Spiolto Respimat demonstrated an improvement compared with placebo at week 12 in mean SGRQ total score (primary endpoint) of -4.9 (95%CI: -6.9, -2.9; p < 0.0001) and -4.6 (95%CI: -6.5, -2.6; p < 0.0001). In a pooled supportive analysis of the 12-week trials, the proportion of patients with a clinically meaningful decrease in SGRQ total score (defined as a decrease of at least 4 units from baseline) at week 12 was greater for Spiolto Respimat (52% [206/393]) compared with tiotropium 5 microgram (41% [159/384]; odds ratio: 1.56 (95%CI: 1.17, 2.07), p = 0.0022) and placebo (32% [118/370]; odds ratio: 2.35 (95%CI: 1.75, 3.16), p < 0.0001).

Inspiratory capacity, breathing discomfort and exercise endurance.

The effect of Spiolto Respimat on inspiratory capacity, breathing discomfort and symptom-limited exercise endurance was investigated in three randomised, double-blind trials in COPD patients:
(i) two replicate, 6 week cross-over trials comparing Spiolto Respimat with tiotropium 5 microgram, olodaterol 5 microgram and placebo during constant work rate cycling (450 received Spiolto Respimat) [Trials 4 and 5];
(ii) one 12 week parallel group trial comparing Spiolto Respimat with placebo during constant work rate cycling (139 received Spiolto Respimat) and constant speed walking (subset of patients) [Trial 6].
Spiolto Respimat significantly improved inspiratory capacity compared to tiotropium 5 microgram, olodaterol 5 microgram and placebo after 6 weeks (Trials 4 and 5; Table 10) and compared to placebo after 12 weeks (0.234 L, p < 0.0001; 95% CI: 0.133, 0.336; Trial 6).
In Trials 4 and 5, Spiolto Respimat improved endurance time during constant work rate cycling by 20.9% and 13.4% compared to placebo (Table 11). In Trial 6, Spiolto Respimat improved endurance time during constant work rate cycling by 12.6% after the first dose (in a subset of patients), by 22.9% after 6 weeks and by 13.8% after 12 weeks compared to placebo. The endurance time during constant speed-walking (in a subset of patients) increased by 20.6% after 6 weeks and by 20.9% after 12 weeks compared to placebo, although the result was not statistically significant (Table 12).
In Trials 4 and 5, Spiolto Respimat decreased the slope of breathing discomfort during constant work rate cycling compared to placebo (nominal p < 0.0005; Table 13).

5.2 Pharmacokinetic Properties

When tiotropium and olodaterol were administered in combination by the inhaled route, the pharmacokinetic parameters for each component were similar to those observed when each active substance was administered separately.
Tiotropium and olodaterol demonstrate linear pharmacokinetics in the therapeutic range. On repeated once-daily inhalation administration, steady-state of tiotropium is reached by day 7. Steady state of olodaterol is achieved after 8 days of once-daily inhalation, and accumulation is up to 1.8-fold as compared to a single dose.

Absorption.

Tiotropium.

Following inhalation by young healthy volunteers, urinary excretion data suggest that approximately 33% of the dose inhaled via the Respimat inhaler reaches the systemic circulation. Oral solutions of tiotropium have an absolute bioavailability of 2% to 3%. Food is not expected to influence the absorption of tiotropium. Maximum tiotropium plasma concentrations were observed 5-7 minutes after the inhalation via Respimat. At steady state, peak tiotropium plasma concentrations of 10.5 picogram/mL were achieved in COPD patients and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 1.60 picogram/mL.

Olodaterol.

Olodaterol is rapidly absorbed, reaching maximum plasma concentrations generally within 10 to 20 minutes following drug inhalation. In healthy volunteers, the absolute bioavailability of olodaterol following inhalation was estimated to be approximately 30%, whereas the absolute bioavailability was below 1% when given as an oral solution. Thus, the systemic availability of olodaterol after inhalation is mainly determined by lung absorption, while any swallowed portion of the dose only negligibly contributes to systemic exposure.

Distribution.

Tiotropium.

Tiotropium 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.

Olodaterol.

Olodaterol exhibits multi-compartmental disposition kinetics after inhalation as well as after intravenous administration. The volume of distribution is high (1,110 L), suggesting extensive distribution into tissue. In vitro binding of [14C] olodaterol to human plasma proteins is independent of concentration and is approximately 60%.

Metabolism.

Tiotropium.

Metabolism does not occur to any great extent, as indicated by 74% renal excretion of unchanged drug after an intravenous dose in young healthy volunteers. 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 CYP 3A4 inhibitors ketoconazole and gestodene.
Tiotropium, even in supra-therapeutic concentrations, does not inhibit CYP 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.

Olodaterol.

Olodaterol is substantially metabolised by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. Of the six metabolites identified, only the unconjugated demethylation product (SOM 1522) binds significantly to beta2-receptors. This metabolite however is not detectable in plasma after chronic inhalation of the recommended therapeutic dose or doses of up to 4-fold higher.
Olodaterol thus is considered the only compound relevant for pharmacological action.
Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7 and 1A9 were shown to be involved in the formation of olodaterol glucuronides.

Excretion.

Tiotropium.

The effective half-life of tiotropium ranges between 27 and 45 hours following inhalation by COPD patients. 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 COPD patients, 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. 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.

Olodaterol.

Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 mL/min. The terminal half-life following intravenous administration is 22 hours. The terminal half-life following inhalation in contrast is about 45 hours, indicating that the latter is determined by absorption rather than by elimination processes.
Following intravenous administration of [14C]-labelled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in faeces. The amount of unchanged olodaterol recovered in the urine after intravenous administration was 19%. Following oral administration, only 9% of the radioactivity was recovered in urine, while the major portion was recovered in faeces (84%). More than 90% of the dose was excreted within 6 and 5 days following intravenous and oral administration, respectively. Following inhalation, excretion of unchanged olodaterol in urine within the dosing interval in healthy volunteers at steady state accounted for 5-7% of the dose.

Pharmacokinetics in special patient groups.

Tiotropium.

As expected for all predominantly renally excreted drugs, advancing age was associated with a decrease of tiotropium renal clearance from 347 mL/min in COPD patients < 65 years to 275 mL/min in COPD patients ≥ 65 years. Exposure to tiotropium was not found to differ with age in patients with asthma.

Olodaterol.

A pharmacokinetic meta-analysis was performed utilising data from 2 controlled clinical trials that included 405 patients with COPD and 296 patients with asthma who received treatment with olodaterol Respimat. The analysis showed that no dose adjustment is necessary based on the effect of age, gender and weight on systemic exposure in COPD patients after inhalation of olodaterol Respimat.
Renal insufficiency.

Tiotropium.

Following once daily inhaled administration of tiotropium to steady-state in COPD patients 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 patients with normal renal function (CLCR > 80 mL/min). In COPD patients with moderate to severe renal impairment (CLCR < 50 mL/min) intravenous administration of tiotropium resulted in a doubling of the total exposure (82% higher AUC0-4h and 52% higher Cmax) compared to COPD patients with normal renal function, which was confirmed by plasma concentrations after dry powder inhalation.

Olodaterol.

In subjects with severe renal impairment (CLCR < 30 mL/min), systemic exposure to olodaterol was on average 1.4-fold increased. This magnitude of exposure increase does not raise any safety concerns given the safety experience of treatment with olodaterol in clinical studies of up to one year at doses up to twice the recommended therapeutic dose.
Hepatic insufficiency.

Tiotropium.

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.

Olodaterol.

In subjects with mild and moderate hepatic impairment, systemic exposure to olodaterol was not affected. The effect of severe hepatic impairment on systemic exposure to olodaterol was not investigated.
Race. Comparison of pharmacokinetic data within and across studies with olodaterol revealed a trend for higher systemic exposure in Japanese and other Asians than in Caucasians.
No safety concerns were identified in clinical studies with olodaterol in Caucasians and Asians of up to one year with olodaterol doses up to twice the recommended therapeutic dose.

Drug-drug interactions.

Olodaterol. Drug-drug interaction studies were carried out using fluconazole as model inhibitor of CYP 2C9 and ketoconazole as potent P-gp and CYP inhibitor.

Fluconazole.

Co-administration of 400 mg fluconazole once daily for 14 days had no relevant effect on systemic exposure to olodaterol.

Ketoconazole.

Co-administration of 400 mg ketoconazole once daily for 14 days increased olodaterol Cmax by 66% and AUC0-1 by 68%.

5.3 Preclinical Safety Data

Genotoxicity.

In vitro mutagenicity for tiotropium or olodaterol alone did not show any genotoxic potential. In the in vivo rat bone marrow micronucleus assay, after inhalational doses up to 2,266+2,174 microgram/kg/day tiotropium+olodaterol for 4 weeks (dose ratio 1:1), the combination was free of genotoxic potential.

Tiotropium.

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).

Olodaterol.

There was no evidence for genotoxicity for olodaterol in standard in vitro (bacterial reverse mutation, mammalian forward mutation) and in vivo rat bone marrow micronucleus assay after inhalational doses up to 1,360 microgram/kg/day for 4 weeks (plasma AUC 1,100 times the anticipated clinical exposure). An increased frequency of micronuclei in rats after single intravenous doses of 10 mg/kg or greater was likely related to drug enhanced (compensatory) erythropoiesis, and is unlikely to be relevant at clinical exposures.

Carcinogenicity.

No carcinogenicity studies for the combination were performed.

Tiotropium.

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 16x (rat) greater than the maximum recommended human daily dose of the drug, based on body surface area.

Olodaterol.

Lifetime treatment of rats induced class- and rodent-specific leiomyomas of the mesovarium at exposures approximately 213-fold the anticipated plasma AUC in adults at the dose of 5 microgram once daily. Lifetime treatment of mice induced class- and rodent-specific smooth muscle tumours (leiomyomas, leiomyosarcomas) of the uterus and incidences of sex cord stromal focal hyperplasia and luteal focal hyperplasia in the ovary at exposures approximately 40- to 400-fold the AUC in adults at the dose of 5 microgram once daily. These findings are not considered to indicate a carcinogenic hazard to patients.

6 Pharmaceutical Particulars

6.1 List of Excipients

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.
Spiolto Respimat cartridge should be used within 3 months after inserting in the Spiolto 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 30°C. 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 Spiolto Respimat re-usable inhaler and 1 Spiolto Respimat cartridge, providing 60 puffs (30 doses).

Triple pack.

1 Spiolto Respimat re-usable inhaler and 3 Spiolto Respimat cartridges, providing 60 puffs (30 doses) each.

Single refill pack.

1 Spiolto Respimat cartridge, providing 60 puffs (30 doses).

Triple refill pack.

3 Spiolto 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.
Olodaterol hydrochloride is a white to off-white powder. It is freely soluble in methanol, soluble in ethanol, sparingly soluble in acetone and slightly soluble in 2-propanol. Dissociation constants: pKa1 = 9.3; pKa2 = 10.1. Partition coefficient: Log Pow (free base) = 3.0; Log D (pH 7.4) = 1.2.

Chemical structure.

Tiotropium bromide monohydrate.

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: free base anhydrous: C19H22NO4S2Br; monohydrate: C19H22NO4S2Br.H2O.
Molecular weight: free base anhydrous: 472.4; monohydrate: 490.4.

Olodaterol hydrochloride.

Chemical name: 2H-1,4-Benzoxazin-3H(4H)-one, 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2- (4-methoxyphenyl)-1,1-dimethylethyl] amino]ethyl]-,monohydrochloride.
Molecular formula: free base anhydrous: C21H26N2O5; hydrochloride salt: C21H26N2O5xHCl.
Molecular weight: free base anhydrous: 386.45; hydrochloride salt: 422.91.
Stereochemistry: (R) enantiomer.

CAS number.

Tiotropium bromide monohydrate.

139404-48-1.

Olodaterol hydrochloride.

869477-96-3.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes