Consumer medicine information

Trelegy Ellipta

Fluticasone furoate; Umeclidinium; Vilanterol

BRAND INFORMATION

Brand name

Trelegy Ellipta

Active ingredient

Fluticasone furoate; Umeclidinium; Vilanterol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Trelegy Ellipta.

SUMMARY CMI

TRELEGY ELLIPTA

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 TRELEGY ELLIPTA?

TRELEGY ELLIPTA contains the active ingredients fluticasone furoate, umeclidinium (as bromide) and vilanterol (as trifenatate). TRELEGY ELLIPTA is used to treat asthma and chronic obstructive pulmonary disease (COPD). For more information, see Section 1. Why am I using TRELEGY ELLIPTA? in the full CMI.

2. What should I know before I use TRELEGY ELLIPTA?

Do not use if you have ever had an allergic reaction to TRELEGY ELLIPTA or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. TRELEGY ELLIPTA should not be used in children or adolescents under the age of 18 years.

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

3. What if I am taking other medicines?

Some medicines may interfere with TRELEGY ELLIPTA and affect how it works.
A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use TRELEGY ELLIPTA?

  • The usual dose is one inhalation once a day. Use TRELEGY ELLIPTA at the same time each day.

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

5. What should I know while using TRELEGY ELLIPTA?

Things you should do
  • Remind any Healthcare Professional (HCP) you visit that you are using TRELEGY ELLIPTA.
  • Contact your doctor if you are concerned about any side effects.
  • Tell your doctor immediately if you become or intend to become pregnant while using TRELEGY ELLIPTA.
  • Tell your doctor if you feel you are getting breathless or wheezy more often than normal, or if you are using a quick-acting inhaler (such as VENTOLIN/salbutamol) more than usual.
Things you should not do
  • Do not stop using this medicine suddenly or change the dosage without checking with your doctor.
  • Do not take any other medicines to help you breathe without checking with your doctor.
Driving or using machines
  • Be careful driving or operating machinery until you know how TRELEGY ELLIPTA affects you.
Looking after your medicine
  • Do not open the foil lid until you are ready to use the inhaler for the first time. Once TRELEGY ELLIPTA has been removed from the tray, you may store it for a maximum period of one month or when your counter reads "0", whichever occurs first.
  • Store TRELEGY ELLIPTA in a cool dry place (below 30°C) away from moisture, heat, or sunlight.
  • If you store TRELEGY ELLIPTA in the refrigerator, allow the inhaler to return to room temperature for at least 1 hour before you use it.

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

6. Are there any side effects?

Less serious side effects include common cold, oral thrush, infection of the nose, sinuses or throat, infection of the upper airways or viral respiratory tract infection, headache, changes in taste, tremor, cough, oropharyngeal pain, hoarseness, itchy, runny or blocked nose, pain in the back of the mouth and throat, inflammation of the sinuses, bronchitis, influenza, dry mouth, constipation, hyperglycaemia, painful or discomfort passing urine and frequent urination, joint pain, back pain, weakening of the bones leading to fractures, muscle spasms or anxiety. Serious side effects include eye disorders, cardiac disorders, allergic reaction, pneumonia, immediate breathing difficulties or wheezing. 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

TRELEGY ELLIPTA

Active ingredient(s): Fluticasone furoate 100 or 200 micrograms, umeclidinium (as bromide) 62.5 micrograms and vilanterol (as trifenatate) 25 micrograms per inhalation

Consumer Medicine Information (CMI)

This leaflet provides important information about using TRELEGY ELLIPTA. You should also speak to your Healthcare Professional (HCP) if you would like further information or if you have any concerns or questions about using TRELEGY ELLIPTA.

Where to find information in this leaflet:

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

1. Why am I using TRELEGY ELLIPTA?

TRELEGY ELLIPTA contains the active ingredients fluticasone furoate, umeclidinium (as bromide) and vilanterol (as trifenatate). Fluticasone furoate belongs to a group of medicines called corticosteroids, often simply called steroids. Umeclidinium and vilanterol belong to a group of medicines called bronchodilators.

TRELEGY ELLIPTA is used to treat adults with asthma and chronic obstructive pulmonary disease (COPD).

Asthma is a condition affecting the lungs. Symptoms of asthma include shortness of breath, wheezing, chest tightness and cough. Two main causes of asthma symptoms are bronchoconstriction (tightening of the muscle surrounding the airways) and inflammation (swelling and irritation of the airways).

Chronic obstructive pulmonary disease (COPD) is a long-term condition affecting the lungs. Symptoms of COPD include shortness of breath, cough, chest discomfort and coughing up phlegm. The COPD symptoms are mainly due to bronchoconstriction (tightening of the muscle surrounding the airways) and inflammation (swelling and irritation of the airways).

Inhaled corticosteroids are used to reduce inflammation. They reduce the swelling and irritation in the small air passages in the lungs and so ease breathing problems. Inhaled corticosteroids also help to prevent attacks of asthma.

Bronchodilators relax the muscles of the small air passages in the lungs. This helps to open the airways and makes it easier for air to get in and out of the lungs. When it is used regularly, it helps the small air passages to remain open.

When TRELEGY ELLIPTA is used regularly, it can help to control your breathing difficulties.

TRELEGY ELLIPTA should not be used to relieve a sudden attack of breathlessness or wheezing. If you get this sort of attack, you must use a quick-acting inhaler (such as VENTOLIN/salbutamol).

Your doctor may have prescribed TRELEGY ELLIPTA for another reason.

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

This medicine is not addictive.

This medicine is available only with a prescription.

2. What should I know before I use TRELEGY ELLIPTA?

Warnings

Do not use TRELEGY ELLIPTA if:

  • you are allergic (hypersensitive) to fluticasone furoate, umeclidinium, vilanterol, or any of the ingredients listed at the end of this leaflet.
  • you are allergic (hypersensitive) to lactose or milk protein.
  • the expiry date printed on the pack has passed or if the packaging is torn or show signs of tampering.

Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have any other medical conditions.
  • take any medicines for any other condition.
  • have been diagnosed with an intolerance to some sugars, or to milk protein.
  • have liver disease, as you may be more likely to have side effects. If you have moderate or severe liver disease, your doctor will limit your dose to the lower strength of TRELEGY ELLIPTA (100/62.5/25 micrograms once daily).
  • have heart problems or high blood pressure.
  • if you have ever been told you have diabetes or high blood sugar.
  • are being treated or have ever been treated for tuberculosis (TB), pneumonia or any other long-standing or untreated infections.
  • have eye problems such as glaucoma or cataracts.
  • have an enlarged prostate, difficulty passing urine or a blockage in your bladder.
  • have weak bones (osteoporosis).
  • have any type of viral, bacterial, or fungal infection.
  • have a problem with your immune system.

Your doctor should give you a personal Action Plan to help manage your asthma or COPD. This plan will include what medicines to take regularly to control your asthma or COPD, as well as what "reliever" medicines to use when you have sudden attacks of breathlessness or wheezing.

Ask your doctor if you have any questions about your Action Plan.

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

Check with your doctor if you are pregnant or intend to become pregnant.

TRELEGY ELLIPTA is not usually recommended for use during pregnancy. Your doctor will weigh up the benefits to you against the potential risks to your baby when considering the use of TRELEGY ELLIPTA during your pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known whether the ingredients of TRELEGY ELLIPTA can pass into breast milk.

Children and adolescents

  • TRELEGY ELLIPTA should not be used in children or adolescents under the age of 18 years.

3. What if I am taking other medicines?

Tell your Healthcare Professional (HCP) if you are taking any other medicines, including any medicines, vitamins, or supplements that you buy without a prescription from your pharmacy, supermarket, or health food shop. This should include all of the medicines that you are using for your asthma or COPD.

Some medicines may interfere with TRELEGY ELLIPTA and affect how it works or make it more likely that you will have side effects.

These medicines include:

  • ketoconazole, to treat fungal infections.
  • ritonavir, to treat viral infections.
  • other long-acting medicines similar to this medicine that are used to treat breathing problems (i.e. inhalers used as maintenance or preventer therapy).
  • medicines to treat depression or mood/mental disorders (such as monoamine oxidase inhibitors or tricyclic depressants).

Medicines that should be avoided:

  • A class of medicines known as "beta-blockers" used to treat high blood pressure or a heart condition.

Medicines which are similar to TRELEGY ELLIPTA should not be used together as an overdose may result.

Check with your Healthcare Professional (HCP) if you are not sure about what medicines, vitamins or supplements you are taking and if these affect TRELEGY ELLIPTA.

4. How do I use TRELEGY ELLIPTA?

How much to use

  • Always use TRELEGY ELLIPTA exactly as your doctor has told you to. Check with your Healthcare Professional (HCP) if you are not sure.

Asthma:

  • The dose for asthma is one inhalation of TRELEGY ELLIPTA 100/62.5/25 micrograms once daily, at the same time each day OR one inhalation of TRELEGY ELLIPTA 200/62.5/25 micrograms once daily, at the same time each day.
  • Your doctor will decide which strength of TRELEGY ELLIPTA is required to treat your asthma.

COPD:

  • The dose for COPD is one inhalation of TRELEGY ELLIPTA 100/62.5/25 micrograms once daily at the same time each day.
  • The higher strength of TRELEGY ELLIPTA 200/62.5/25 micrograms is not suitable for the treatment of COPD.

When to use TRELEGY ELLIPTA

  • Use TRELEGY ELLIPTA once daily at the same time each day.
  • It is very important that you use TRELEGY ELLIPTA every day, as instructed by you Healthcare Professional (HCP). This will help to keep you free of symptoms throughout the day and night.
  • Use TRELEGY ELLIPTA for as long as your Healthcare Professional (HCP) recommends. It will only be effective as long as you are using it. Do not stop unless your Healthcare Professional (HCP) advises you to, even if you feel better.

How to use TRELEGY ELLIPTA

  • To use TRELEGY ELLIPTA, you breathe it into your lungs through your mouth using the Ellipta inhaler.
  • The full instructions for using TRELEGY ELLIPTA are given on a leaflet inside the pack. A brief summary of the instructions is provided below.
  • TRELEGY ELLIPTA is ready to use straight away. No preparation or checks of the inhaler are required.
  • Do not open TRELEGY ELLIPTA until you are ready to inhale a dose of medicine.

Step 1: Prepare a dose

  • Wait to open the cover until you are ready to take your dose. Slide the cover fully down until you hear a "click".
  • If the dose counter does not count down as you hear the "click", the inhaler will not deliver medicine. Take it back to your pharmacist for advice.
  • Do not shake the inhaler at any time.

Step 2: Inhale your medication

  • While holding the inhaler away from your mouth, breathe out as far as is comfortable.
  • Do not breathe out into the inhaler.
  • Put the mouthpiece between your lips and close your lips firmly around it.
  • Do not block the air vent with your fingers.

  • Take one long, steady, deep breath in. Hold this breath for about 3-4 seconds or as long as is comfortable.
  • Remove the inhaler from your mouth.
  • Breathe out slowly and gently away from the mouthpiece.
  • You may not be able to taste or feel the medicine, even when you are using the inhaler correctly.
  • After using TRELEGY ELLIPTA, you may clean the mouthpiece, using a dry tissue, before you close the cover.

Step 3: Close the inhaler and rinse your mouth

  • Slide the cover upwards as far as it will go, to cover the mouthpiece.

  • Rinse your mouth out with water without swallowing after you have used the inhaler. This will make it less likely that you will develop a sore mouth or throat as side effects.

If you forget to use TRELEGY ELLIPTA

TRELEGY ELLIPTA should be used regularly at the same time each day. If you miss your dose at the usual time, skip the dose you missed and use your next dose when you are meant to. Otherwise, use it as soon as you remember, then go back to using it as you would normally.

Do not take a double dose to make up for the dose you missed.

  • If you are not sure what to do, ask your Healthcare Professional (HCP).
  • If you have trouble remembering to take your medicine, ask your pharmacist for some hints.
  • If you become wheezy, or breathless, or develop any other symptoms of an asthma attack, use your quick-acting inhaler (e.g. VENTOLIN/salbutamol), then seek medical advice.

If you use too much TRELEGY ELLIPTA (overdose)

If you think that you have used too much TRELEGY ELLIPTA, you may need urgent medical attention. You may notice that your heart is beating faster than usual, you feel shaky or have a headache.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26 in Australia), 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.

If you have used larger doses than instructed for a long period of time, it is particularly important that you ask your Healthcare Professional (HCP) for advice. This is because larger doses of TRELEGY ELLIPTA may reduce the amount of steroid hormones produced naturally by your body.

5. What should I know while using TRELEGY ELLIPTA?

Things you should do

  • Remind any Healthcare Professional (HCP) you visit that you are using TRELEGY ELLIPTA, especially if you are about to be started on any new medicine.
  • Use TRELEGY ELLIPTA for as long as your doctor recommends. It will only be effective as long as you are using it. Do not stop unless your doctor advises you to, even if you feel better.
  • Check with your doctor if you are unsure about which medicines for asthma or COPD you should continue taking while being treated with TRELEGY ELLIPTA.
  • Continue to use a quick-acting inhaler (such as VENTOLIN/salbutamol) during an acute episode.
  • If you are about to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.
  • Keep all of your doctor's appointments so that your progress can be checked.

Call your doctor straight away if you:

  • experience blurred vision or other visual disturbances.
  • experience increased thirst, frequent urination, or unexplained tiredness (signs of high blood sugar).
  • become pregnant while taking this medicine.
  • feel that your breathing or wheezing gets worse straight after using TRELEGY ELLIPTA. Stop using it immediately.

Please see Section 6. Are there any side effects? for more instances in which you should contact your doctor.

Things you should not do

  • Do not stop using this medicine suddenly or change the dosage without medical advice.
  • Do not use TRELEGY ELLIPTA to treat any other complains unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • If you are currently on oral or injectable corticosteroids, do not stop taking these medicines suddenly without checking with your doctor.
  • Do not use any other long-acting inhalers which contain inhaled corticosteroids or bronchodilators.
  • Do not take any other medicines for your breathing problems without checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how TRELEGY ELLIPTA affects you.

This medicine is not expected to affect your ability to drive a car or operate machinery.

Action Plan

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

Looking after your medicine

  • Store in the original package container in order to protect from moisture and do not open the foil lid until you are ready to inhale for the first time.
  • If you store in a refrigerator, allow the inhaler to return to room temperature for at least an hour before use.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight where the temperature stays below 30°C.

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.

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

When to discard your medicine

Ask your pharmacist to safely throw away TRELEGY ELLIPTA one month after you open the foil tray or when the counter reads "0", whichever comes first. Write the date the inhaler should be discarded on the label in the space provided. The date should be added as soon as the inhaler has been removed from the tray.

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 or if the packaging is torn or shows signs of tampering.

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.

Your doctor will consider the risk of side effects when deciding which strength of TRELEGY ELLIPTA you should use.

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

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

Less serious side effects

Less serious side effectsWhat to do
Nervous system disorders:
  • headache
  • changes in taste
  • tremor
  • feelings of anxiety
Infections:
  • common cold
  • infection of the nose, sinuses or throat
  • infection of the upper airways or viral respiratory tract infection
  • flu (influenza)
Respiratory, thoracic and mediastinal disorders:
  • cough
  • oropharyngeal pain
  • hoarseness
  • itchy, runny, or blocked nose
  • pain and irritation in the back of the mouth and throat
  • feeling pressure or pain in the cheeks and forehead (may be a sign of inflammation of the sinuses known as sinusitis)
  • inflammation of the lungs (bronchitis)
Musculoskeletal and connective tissue disorders:
  • joint and back pain
  • muscle spasms
Gastrointestinal disorders:
  • dry mouth
  • constipation
Speak to your doctor if you have any of these less serious side effects and they worry you.
Less serious side effects that require medical intervention. Please consult your doctor if you experience any of the following:
  • sore, raised patches in the mouth or throat caused by a fungal infection (oral thrush)
  • increase in blood sugar (hyperglycaemia). This may lead to increased thirst, frequent urination, or unexplained tiredness
  • painful or discomfort passing urine and frequent urination (may be signs of a urinary tract infection)
  • you have been told that you have weakening of the bones, leading to risk of fractures
Contact your doctor if you experience any of these less serious side effects.

Serious side effects

Serious side effectsWhat to do
Allergic reactions:
  • If you have any of the following symptoms after using TRELEGY ELLIPTA, stop using this medicine and tell your doctor immediately.
  • Symptoms of an allergic reaction include some or all of the following:
    - shortness of breath
    - wheezing, coughing or difficulty breathing
    - swelling of the face, lips/mouth, tongue, or throat
    - rash, itching, redness, or hives on the skin
    - suddenly feeling weak or light-headed (may lead to collapse or loss of consciousness)
Infection of the lungs (pneumonia):
  • Symptoms include:
    - fever
    - chills
    - increased sputum production
    - change in sputum colour
    - increased cough
    - increased breathing difficulties
Cardiovascular disorders:
  • irregular or fast heartbeat
  • palpitations
Eye disorders:
  • blurred vision or eye pain (possible signs of glaucoma)
  • increased eye pressure
Immediate breathing difficulties and wheezing:
  • If your breathing or wheezing gets worse straight after using TRELEGY ELLIPTA, stop using it immediately, and tell your doctor as soon as possible.
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor 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 before you decide to stop taking any of your medicines.

7. Product details

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

What TRELEGY ELLIPTA contains

Active ingredientFluticasone furoate
Umeclidinium (as bromide)
Vilanterol (as trifenatate)
Other ingredientsLactose monohydrate (contains milk protein)
Magnesium stearate
Potential allergensLactose monohydrate (contains milk protein)
Fluticasone furoate
Umeclidinium (as bromide)
Vilanterol (as trifenatate)

Each dose contains 100 or 200 micrograms of the active ingredient fluticasone furoate. The amount depends on which strength of TRELEGY ELLIPTA you have been given. Each dose also contains the active ingredients 62.5 micrograms of umeclidinium (as bromide) and 25 micrograms of vilanterol (as trifenatate).

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

What TRELEGY ELLIPTA looks like

The Ellipta device itself is a plastic inhaler with a light grey body, a beige mouthpiece cover and a dose counter. It is packaged in a foil laminate tray with a peelable foil lid.

The active substances are present in powder form in separate blister strips inside the inhaler. TRELEGY ELLIPTA contains either 14 or 30 doses on each blister strip. The 14 dose inhaler has 14 blisters on each strip, and the 30 dose inhaler has 30 blisters on each strip, depending on which pack size you have been given.

The tray contains a desiccant sachet, to reduce moisture in the packaging. Once you have opened the lid of the tray, throw the desiccant away - do not open, eat or inhale it.

TRELEGY ELLIPTA 100/62.5/25 micrograms is AUST R 284636.

TRELEGY ELLIPTA 200/62.5/25 micrograms is AUST R 335858.

Who distributes TRELEGY ELLIPTA

GlaxoSmithKline Australia Pty Ltd
Level 4, 436 Johnston Street,
Abbotsford, Victoria, 3067
Phone: 1800 033 109
www.gsk.com.au

Trade marks are owned by or licensed to the GSK group of companies.

© 2024 GSK group of companies or licensor.

This leaflet was prepared in September 2024.

Version 8.0

Published by MIMS December 2024

BRAND INFORMATION

Brand name

Trelegy Ellipta

Active ingredient

Fluticasone furoate; Umeclidinium; Vilanterol

Schedule

S4

 

1 Name of Medicine

Fluticasone furoate/umeclidinium (as bromide)/vilanterol (as trifenatate).

2 Qualitative and Quantitative Composition

Each foil strip contains regularly distributed blisters with one strip containing either 100 microgram or 200 microgram of fluticasone furoate and the other strip containing 62.5 microgram of umeclidinium (equivalent to 74.2 microgram umeclidinium [as bromide]) and 25 microgram of vilanterol (as trifenatate).
Each single inhalation provides a delivered dose (the dose leaving the mouthpiece of the inhaler) containing 92 microgram fluticasone furoate, 55 microgram umeclidinium (equivalent to 65 microgram umeclidinium [as bromide]) and 22 microgram vilanterol (as trifenatate) or 184 microgram fluticasone furoate, 55 microgram umeclidinium (equivalent to 65 microgram umeclidinium [as bromide]) and 22 microgram vilanterol (as trifenatate).

Excipients with known effect.

Lactose monohydrate (which contains milk protein).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for inhalation.
White powder in a light grey inhaler (Ellipta) with a beige mouthpiece cover and a dose counter.

4 Clinical Particulars

4.1 Therapeutic Indications

Asthma.

Trelegy Ellipta is indicated for the maintenance treatment of asthma in adult patients who are not adequately controlled with a combination of inhaled corticosteroid and a long-acting beta2-agonist.

COPD.

Trelegy Ellipta is indicated for the maintenance treatment of adults with moderate to severe COPD who require treatment with LAMA+LABA+ICS.
Trelegy Ellipta is not indicated for the initiation of therapy in COPD.

4.2 Dose and Method of Administration

Patients can be changed from their existing inhalers to Trelegy Ellipta at the next dose. However, it is important that patients do not take other long-acting beta2-receptor agonists (LABA) or long-acting muscarinic receptor antagonists (LAMA) or inhaled corticosteroids (ICS) while taking Trelegy Ellipta.

Dose.

Asthma. Patients should be made aware that Trelegy Ellipta must be used regularly, even when asymptomatic.
If symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.
Patients should be regularly reassessed by a healthcare professional so that the strength of Trelegy Ellipta they are receiving remains optimal and is only changed on medical advice.

Adults.

The recommended dose is one inhalation of Trelegy Ellipta 100/62.5/25 microgram once daily or one inhalation of Trelegy Ellipta 200/62.5/25 microgram once daily.
Trelegy Ellipta 100/62.5/25 microgram should be considered for patients who require a low to mid dose of ICS in combination with a LAMA and a LABA.
Trelegy Ellipta 200/62.5/25 microgram should be considered for patients who require a higher dose of ICS in combination with a LAMA and a LABA.
If patients are inadequately controlled on Trelegy Ellipta 100/62.5/25 microgram, consider increasing the dose to 200/62.5/25 microgram, which may provide additional improvement in asthma control.

Children and adolescents.

The safety and efficacy of Trelegy Ellipta have not been established in children or adolescents less than 18 years of age.
COPD. A stepwise approach to the management of chronic obstructive pulmonary disease (COPD) is recommended, including the cessation of smoking and a pulmonary rehabilitation program. Trelegy Ellipta is not to be used as initial therapy, but may be considered as step-up from LAMA/LABA or ICS/LABA or for patients already taking LAMA+LABA+ICS.

Adults.

The recommended and maximum dose is one inhalation of Trelegy Ellipta 100/62.5/25 once daily. This equates to a maximum daily dose containing fluticasone furoate 100 microgram, umeclidinium (as bromide) 62.5 microgram, and vilanterol (as trifenatate) 25 microgram.

Children and adolescents.

Use in patients less than 18 years of age is not relevant to the COPD indication for this product.

Asthma and COPD.

Special populations.

Elderly population.

No dosage adjustment is required in patients over 65 years (see Section 5.2 Pharmacokinetic Properties).

Renal impairment.

No dosage adjustment is required for patients with renal impairment (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

Caution should be exercised when dosing patients with hepatic impairment who may be more at risk of systemic adverse reactions associated with corticosteroids. For patients with moderate or severe hepatic impairment the maximum dose is 100/62.5/25 microgram (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Method of administration.

Trelegy Ellipta is for oral inhalation only. Trelegy Ellipta should be administered once daily, either morning or evening, but at the same time each day.
After inhalation, the patient should rinse their mouth with water without swallowing.

How to use Trelegy Ellipta.

What is the Ellipta inhaler? Trelegy Ellipta is inhaled through the mouth using the Ellipta inhaler.
When you first use the Ellipta inhaler you do not need to check that it is working properly, and you do not need to prepare it for use in any special way. Just follow these step by step instructions.
The inhaler is packaged in a tray. Do not open the tray until you are ready to inhale a dose of your medicine. When you are ready to use your inhaler, peel back the lid to open the tray. The tray contains a desiccant sachet, to reduce moisture. Throw this desiccant sachet away - do not open, eat or inhale it.
When you take the inhaler out of the sealed tray, it will be in the 'closed' position. Do not open the inhaler until you are ready to inhale a dose of medicine. Write the "Discard by" date on the inhaler label in the space provided. The "Discard by" date is 1 month from the date you open the tray. After this date, the inhaler should no longer be used.
The step-by-step instructions shown below for the 30-dose (30-day supply) Ellipta inhaler also apply to the 14-dose (14-day supply) Ellipta inhaler.
Important information to read before you start. If you open and close the cover without inhaling the medicine, you will lose the dose.
The lost dose will be securely held inside the inhaler, but it will no longer be available.
It is not possible to accidentally take extra medicine or a double dose in one inhalation. See Figure 1.

Step 1: prepare a dose.

Wait to open the cover until you are ready to take your dose.
Do not shake the inhaler.
Slide the cover fully down until you hear a 'click'. See Figure 2.
Your medicine is now ready to be inhaled.
The dose counter counts down by 1 to confirm.
If the dose counter does not count down as you hear the 'click', the inhaler will not deliver medicine.
Take it back to your pharmacist for advice.
Do not shake the inhaler at any time.

Step 2: inhale your medicine.

Whilst holding the inhaler away from your mouth, breathe out as far as is comfortable.
Do not breathe out into the inhaler.
Put the mouthpiece between your lips, and close your lips firmly around it.
Do not block the air vent with your fingers. See Figure 3.
Take one long, steady, deep breath in. Hold this breath for about 3-4 seconds or for as long as is comfortable.
Remove the inhaler from your mouth.
Breathe out slowly and gently away from the mouthpiece.
You may not be able to taste or feel the medicine, even when you are using the inhaler correctly.
If you want to clean the mouthpiece, use a dry tissue, before you close the cover.

Step 3: close the inhaler and rinse your mouth.

Slide the cover upwards as far as it will go, to cover the mouthpiece. See Figure 4.
Rinse your mouth with water without swallowing after you have used the inhaler.
This will make it less likely that you will develop a sore mouth or throat as side effects.

4.3 Contraindications

Trelegy Ellipta is contraindicated in patients with severe milk-protein allergy or who have demonstrated hypersensitivity to fluticasone furoate, umeclidinium, vilanterol or any of the excipients.

4.4 Special Warnings and Precautions for Use

COPD.

Treatment of COPD should be in accordance with relevant clinical guidelines. Patients should have a personal action plan designed in association with their treating physician.

Pneumonia.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of such infections overlap with the symptoms of COPD exacerbations. In line with the known class effect of inhaled corticosteroids, pneumonia events (including pneumonias resulting in hospitalisation) were observed in patients with COPD receiving fluticasone furoate/umeclidinium/vilanterol. In some instances, fatal events of pneumonia have been reported with use of inhaled corticosteroid (fluticasone furoate)-containing drugs (see Section 4.8 Adverse Effects (Undesirable Effects)). Risk factors for pneumonia in patients with COPD receiving inhaled corticosteroid-containing drugs include current smoking status, history of pneumonia, low body mass index and severe COPD. These factors should be considered when Trelegy Ellipta is prescribed, and treatment re-evaluated if pneumonia occurs.
An increased incidence of pneumonia in patients with asthma receiving higher doses of Trelegy Ellipta cannot be excluded. This is based on clinical experience with fluticasone furoate/vilanterol, where there was a trend toward an increased risk of pneumonia for fluticasone furoate/vilanterol 200/25 microgram compared with fluticasone furoate/vilanterol 100/25 microgram and placebo.

Exacerbations.

Trelegy Ellipta should not be used to treat acute asthma symptoms or an acute exacerbation in COPD for which an inhaled short-acting bronchodilator is required.
Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician.
Patients should not stop therapy with Trelegy Ellipta, in asthma or COPD, without physician supervision since symptoms may recur after discontinuation.
Asthma-related adverse events and exacerbations may occur during treatment with Trelegy Ellipta. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of Trelegy Ellipta.

Paradoxical bronchospasm.

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing, and may be life-threatening. Treatment with Trelegy Ellipta should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Cardiovascular effects.

Cardiovascular effects, such as cardiac arrhythmias e.g. atrial fibrillation and tachycardia, may be seen after the administration of muscarinic receptor antagonists or sympathomimetic agents, including umeclidinium or vilanterol, respectively. Therefore Trelegy Ellipta should be used with caution in patients with unstable or life-threatening cardiovascular disease.

Patients with hepatic impairment.

For patients with moderate to severe hepatic impairment receiving Trelegy Ellipta, the 100/62.5/25 microgram dose should be used, and patients should be monitored for systemic corticosteroid-related adverse reactions (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Systemic corticosteroid effects.

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression.
Ocular effects may be reported with systemic and topical corticosteroid use. If a patient presents with a change in vision, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR).
Inhaled corticosteroids should be used with caution in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Antimuscarinic activity.

Consistent with its antimuscarinic activity, Trelegy Ellipta should be used with caution in patients with narrow-angle glaucoma or urinary retention. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g. eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema). Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develops.

Use in the elderly.

There are no special precautions for use in the elderly.

Paediatric use.

Trelegy Ellipta should not be used in children or adolescents.

Effects on laboratory tests.

Interactions with laboratory tests have not been established.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Clinically significant drug interactions mediated by fluticasone furoate, umeclidinium (as bromide) or vilanterol (as trifenatate) at clinical doses are considered unlikely due to the low plasma concentrations achieved after inhaled dosing.

Interaction with beta-blockers.

Beta-adrenergic blockers may weaken or antagonise the effect of beta2-adrenergic agonists, such as vilanterol. Concurrent use of both non-selective and selective beta-blockers should be avoided unless there are compelling reasons for their use.

Interaction with CYP3A4 inhibitors.

Fluticasone furoate and vilanterol are both rapidly cleared by extensive first-pass metabolism mediated by the enzyme CYP3A4.
A repeat-dose study was performed in healthy subjects with the fluticasone furoate/vilanterol combination (200/25 microgram) and ketoconazole (400 milligram, a strong CYP3A4 inhibitor and P-gp inhibitor). Co-administration increased mean fluticasone furoate AUC(0-24) and Cmax by 36% and 33%, respectively. The increase in fluticasone furoate exposure was associated with a 27% reduction in 0-24 hours weighted mean serum cortisol. Co-administration increased mean vilanterol AUC(0-t) and Cmax by 65% and 22%, respectively. The increase in vilanterol exposure was not associated with an increase in beta-agonist related systemic effects on heart rate or blood potassium.
Care is advised when co-administering with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) as there will be increased systemic exposure to both fluticasone furoate and vilanterol, which could lead to an increase in the potential for adverse reactions (see Section 5.2 Pharmacokinetic Properties).

Interaction with P-glycoprotein inhibitors.

Fluticasone furoate, umeclidinium and vilanterol are substrates of P-gp. A repeat dose drug interaction study performed in healthy subjects who were administered with umeclidinium/vilanterol or umeclidinium, and the P-gp and moderate CYP3A4 inhibitor verapamil (240 milligram), did not show any clinically significant effect on the pharmacokinetics of vilanterol or umeclidinium.

Interaction with CYP2D6 inhibitors.

Umeclidinium is a substrate of CYP2D6 enzyme. The effect of a CYP2D6-poor metaboliser genotype on the steady-state pharmacokinetics of umeclidinium was assessed in healthy volunteers (CYP2D6 normal metabolisers and CYP2D6 poor metabolisers). No clinically meaningful difference in systemic exposure to umeclidinium (500 microgram) was observed following repeat daily inhaled dosing to normal and CYP2D6-poor metaboliser subjects.

Interaction with sympathomimetic medicinal products.

Concomitant administration of other sympathomimetic agents (alone or as part of combination therapy) may potentiate the undesirable effects of Trelegy Ellipta. Trelegy Ellipta should not be used in conjunction with other LABAs or medicinal products containing LABAs.

Interaction with monoamine oxidase inhibitors and tricyclic antidepressants.

Vilanterol, like other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.

Other LAMAs and LABAs.

Co-administration of Trelegy Ellipta with other LAMAs or LABAs has not been studied and is not recommended as it may potentiate the adverse reactions (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.9 Overdose).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effects of Trelegy Ellipta on human fertility. Studies in rats showed no effect of fluticasone furoate, umeclidinium or vilanterol on male or female fertility at doses of the individual agents producing large or very large multiples of the systemic exposure in humans.
(Category B3)
There are insufficient data from the use of fluticasone furoate/umeclidinium/vilanterol in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels.
Fluticasone furoate was not teratogenic in studies by the inhalational route in rats and rabbits, but it caused decreased fetal weight and impaired ossification in rats (at 91 microgram/kg/day) and abortion in rabbits (at doses of 47 microgram/kg/day and greater), occurring in conjunction with maternotoxicity. There were no adverse effects on embryofetal development in rats at 23 microgram/kg/day, yielding systemic exposure approximately 3-fold the human clinical exposure at 184 microgram delivered dose of fluticasone furoate (the maximum recommended dose in patients with asthma) based on AUC, and there were no developmental effects in a prenatal and postnatal study in rats (at doses up to 27 microgram/kg/day).
Embryofetal development was unaffected by umeclidinium in rats treated at up to 278 microgram/kg/day by inhalation (estimated to yield almost 40-fold the human clinical exposure at 55 microgram delivered dose of umeclidinium per day) and in rabbits treated at up to 306 microgram/kg/day by inhalation or up to 180 microgram/kg/day subcutaneously (yielding approximately 27- and 150-fold the plasma AUC in patients). In a pre- and post-natal study, subcutaneous administration of umeclidinium to rats resulted in lower maternal body weight gain and food consumption and slightly decreased pre-weaning pup body weights in dams given 180 microgram/kg/day (equivalent to approximately 61-fold the human clinical exposure at 55 microgram delivered dose of umeclidinium, based on AUC).
In rabbits, there was evidence of maternal toxicity and embryotoxicity following inhalation exposure to vilanterol (as trifenatate) at 591 and 62.7 microgram/kg/day, respectively (equivalent to 118- and 10-fold the clinical exposure at 22 microgram/day delivered dose of vilanterol, based on AUC). A non-dose related increase in malformations, including the rare open eyelid, was also observed. In a separate study with subcutaneous exposure, increased incidence of open eye and increase in skeletal variations (indicative of developmental delay) occurred at 300 microgram/kg/day (equivalent to approximately 845-fold the clinical exposure at 22 microgram/day delivered dose of vilanterol based on AUC) with a NOAEL of 30 microgram/kg/day (equivalent to 62-fold the clinical exposure at 22 microgram/day delivered dose of vilanterol based on AUC). Vilanterol had no adverse effect on pre- or post-natal development in rats.
Trelegy Ellipta should be used during pregnancy only if the expected benefit to the mother justifies the potential risk to the fetus.
 It is unknown whether fluticasone furoate, umeclidinium, vilanterol or their metabolites are excreted in human milk. However, other corticosteroids, muscarinic antagonists and beta2-agonists are detected in human milk. A risk to breast-fed newborns/infants cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue Trelegy Ellipta therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of fluticasone furoate/umeclidinium/vilanterol on the ability to perform tasks that require judgement, motor or cognitive skills.
A detrimental effect on such activities would not be anticipated from the pharmacology of fluticasone furoate, umeclidinium (as bromide) or vilanterol (as trifenatate) at clinical doses.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The safety profile of Trelegy Ellipta (fluticasone furoate/umeclidinium/vilanterol) is based on data from one phase III clinical study in asthma (205715) and two phase III clinical studies in COPD (CTT116853 and CTT116855).
Asthma. The asthma study (205715) included 2,436 adult subjects inadequately controlled on their current treatment of combination therapy (ICS plus a LABA) who received fluticasone furoate/umeclidinium/vilanterol or an active comparator of fluticasone furoate/vilanterol for 24 to 52 weeks' duration.

Study 1 (205715).

Adverse effects following 24 to 52 weeks of treatment with fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 microgram or fluticasone furoate/umeclidinium/vilanterol 200/62.5/25 microgram are presented in Table 1.
COPD. The first study (CTT116853, FULFIL) included 911 patients with COPD who received doses of fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 microgram once daily for up to 24 weeks, of whom 210 patients received fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 microgram once daily for up to 52 weeks, with an active comparator, budesonide/formoterol 400/12 microgram twice daily.
The second study (CTT116855, IMPACT) included 4,151 patients with COPD who received fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 microgram once daily for up to 52 weeks, with two active comparators, fluticasone furoate/vilanterol (FF/VI 100/25 microgram) and umeclidinium/vilanterol (UMEC/VI 62.5/25 microgram).

Study 1 (CTT116853).

Adverse events following 24 weeks of treatment are presented in Table 2.
In a subset of subjects, in addition to adverse events reported in Table 2, adverse events occurring at a rate of greater than or equal to 1% in subjects receiving fluticasone furoate/umeclidinium/vilanterol for up to 52 weeks (n = 210) were viral respiratory tract infection, oropharyngeal pain and hypertension.

Study 2 (CTT116855, IMPACT).

The most frequently reported adverse events are presented in Table 3.
Adverse reactions are listed by MedDRA system organ class and by frequency (see Table 4). Where adverse reaction frequencies differed between studies and populations, the higher frequency is reported. The following convention has been used for the classification of adverse reactions:
Very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1000 to < 1/100; rare: ≥ 1/10,000 to < 1/1000; very rare: < 1/10,000.

Description of selected adverse reactions.

*Pneumonia (see Section 4.4 Special Warnings and Precautions for Use).

COPD.

In Study CTT116853 which had a total of 1810 patients with COPD FEV1 45% of predicted (standard deviation [SD] 13%) (mean post bronchodilation), 65% of whom had experienced a moderate/severe COPD exacerbation in the year prior to study entry, a higher incidence of pneumonia events was reported in patients receiving fluticasone furoate/umeclidinium/vilanterol (20 patients, 2%) than in patients receiving budesonide/formoterol (7 patients, < 1%). Pneumonia which required hospitalisation occurred in 1% of patients receiving fluticasone furoate/umeclidinium/vilanterol and < 1% of patients receiving budesonide/formoterol up to 24 weeks. One fatal case of pneumonia was reported in a patient who received fluticasone furoate/umeclidinium/vilanterol, however this was not considered to be related to the study treatment. However, in the subset of 430 patients treated for up to 52 weeks, the incidence of pneumonia events reported in the fluticasone furoate/umeclidinium/vilanterol and budesonide/formoterol arms was equal at 2%.
In a 52-week study, a total of 10,355 patients with COPD with a history of moderate or severe exacerbations within the prior 12 months (mean post-bronchodilator screening FEV1 46% of predicted, SD 15%) (Study CTT116855), the incidence of pneumonia was 8% for fluticasone furoate/umeclidinium/vilanterol (n=4,151), 7% for fluticasone furoate/vilanterol (n=4,134), and 5% for umeclidinium/vilanterol (n=2,070). Fatal pneumonia occurred in 12 of 4,151 patients (3.5 per 1,000 patient-years) receiving fluticasone furoate/umeclidinium/vilanterol, 5 of 4,134 patients (1.7 per 1,000 patient-years) receiving fluticasone furoate/vilanterol, and 5 of 2,070 patients (2.9 per 1,000 patient-years) receiving umeclidinium/vilanterol.

Asthma.

In patients with asthma (study 205715) treated up to 52 weeks, the incidence of pneumonia was 1% (5 of 406 patients) for fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 microgram and < 1% (4 of 408 patients) for fluticasone furoate/umeclidinium/vilanterol 200/62.5/25 microgram. The incidence of pneumonia was 2% in the fluticasone furoate/vilanterol 100/25 microgram (7 of 407 patients) and fluticasone furoate/vilanterol 200/25 microgram (7 of 406 patients) groups. The incidence of pneumonia events requiring hospitalisation was similar in the fluticasone furoate/umeclidinium/vilanterol and fluticasone furoate/vilanterol groups (< 1% for all groups). There were no fatal pneumonia events.

Post marketing data.

See Table 5.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

No data from clinical studies are available regarding overdose of Trelegy Ellipta.

Symptoms and signs.

An overdose of Trelegy Ellipta may produce signs, symptoms or adverse effects associated with the individual components' pharmacological actions (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

Treatment.

There is no specific treatment for an overdose with Trelegy Ellipta. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
Cardioselective beta-blockade should only be considered for profound vilanterol overdose effects that are clinically concerning and unresponsive to supportive measures. Cardioselective beta-blocking drugs should be used with caution in patients with a history of bronchospasm.
Further management should be as clinically indicated.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs for obstructive airways diseases, Adrenergics in combination with anticholinergics including triple combinations with corticosteroids, ATC code: R03AL08.

Mechanism of action.

Fluticasone furoate, umeclidinium (as bromide) and vilanterol (as trifenatate) represent three classes of medications: a synthetic corticosteroid (presented here as an inhaled corticosteroid [ICS]), a long-acting muscarinic receptor antagonist (also referred to as a LAMA) and a selective, long-acting beta2-receptor agonist (also referred to as a LABA), respectively.

Fluticasone furoate.

Fluticasone furoate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects asthma and COPD symptoms is not known. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g. eosinophils, macrophages, lymphocytes) and mediators (e.g. cytokines and chemokines) involved in inflammation.

Umeclidinium (as bromide).

Umeclidinium (as bromide) is a LAMA. It is a quinuclidine derivative that is a muscarinic receptor antagonist with activity across multiple muscarinic cholinergic receptor subtypes. Umeclidinium exerts its bronchodilatory activity by competitively inhibiting the binding of acetylcholine with muscarinic acetylcholine receptors on airway smooth muscle. It demonstrates slow reversibility at the human M3 muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directly to the lungs in pre-clinical models.

Vilanterol (as trifenatate).

Vilanterol (as trifenatate) is a selective LABA.
The pharmacologic effects of beta2-adrenoceptor agonist drugs, including vilanterol (as trifenatate), are at least in part attributable to stimulation of intracellular adenylate cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Pharmacodynamics.

Cardiovascular effects.

The effect of the triple combination of fluticasone furoate/umeclidinium (as bromide)/vilanterol (as trifenatate) (hereafter referred to as fluticasone furoate/umeclidinium/vilanterol or FF/UMEC/VI) on the QT interval has not been evaluated in a thorough QT (TQT) study. TQT studies for fluticasone furoate/vilanterol and umeclidinium/vilanterol did not show clinically relevant effects on QT interval at clinical doses of fluticasone furoate, umeclidinium and vilanterol (see below).
The effect of umeclidinium/vilanterol on the QT interval was evaluated in a placebo and moxifloxacin controlled QT study involving once daily administration of umeclidinium/vilanterol 125/25 microgram or 500/100 microgram for 10 days in 103 healthy volunteers. The maximum mean difference in prolongations of QT interval (corrected using the Fridericia method, QTcF) from placebo after baseline-correction was 4.3 (90% CI: 2.2, 6.4) milliseconds seen 10 minutes after administration with umeclidinium/vilanterol 125/25 microgram and 8.2 (90% CI: 6.2, 10.2) milliseconds seen 30 minutes after administration with umeclidinium/vilanterol 500/100 microgram. No clinically relevant effect on prolongation of QT interval (corrected using the Fridericia method) was observed.
In addition, no clinically significant effects of umeclidinium/vilanterol on cardiac rhythm were observed on 24-hour Holter monitoring in 281 patients who received umeclidinium/vilanterol 125/25 microgram once daily for up to 12 months.
The effect of fluticasone furoate/vilanterol on the QT interval was evaluated in a double-blind, multiple-dose, placebo- and positive-controlled crossover study in 85 healthy volunteers. The maximum mean (95% upper confidence bound) difference in QTcF from placebo after baseline-correction was 4.9 (7.5) milliseconds and 9.6 (12.2) milliseconds seen 30 minutes after dosing with fluticasone furoate/vilanterol 200/25 microgram and fluticasone furoate/vilanterol 800/100 microgram, respectively. A dose-dependent increase in heart rate was also observed. The maximum mean (95% upper confidence bound) difference in heart rate from placebo after baseline-correction was 7.8 (9.4) beats/min and 17.1 (18.7) beats/min seen 10 minutes after dosing with fluticasone furoate/vilanterol 200/25 microgram and fluticasone furoate/vilanterol 800/100 microgram, respectively.
No clinically relevant effects on the QTc interval were observed on review of centrally-read ECGs from 1,504 subjects with asthma exposed to fluticasone furoate/umeclidinium/vilanterol for up to 24 weeks, or in a subset of 360 subjects exposed for up to 52 weeks.
No clinically relevant effects on the QTc interval were observed on review of centrally-read ECGs from 911 subjects with COPD exposed to fluticasone furoate/umeclidinium/vilanterol for up to 24 weeks, or in a subset of 210 subjects exposed for up to 52 weeks.

Clinical trials.

Asthma. The safety and efficacy of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) were evaluated in 2,436 subjects in a randomised, multi-centre, active-controlled, double-blind clinical trial of 24 to 52 weeks' duration in adult subjects with asthma inadequately controlled on their current treatments of combination therapy (ICS plus a LABA) (Study 205715, CAPTAIN). The trial evaluated the efficacy of FF/UMEC/VI on lung function, annualised rate of moderate and severe asthma exacerbations, asthma symptom control, and health-related quality of life when compared with fluticasone furoate/vilanterol. The primary endpoint was change from baseline in trough Forced Expiratory Volume in 1 second (FEV1) at Week 24. The key secondary endpoint was the annualised rate of moderate/severe asthma exacerbation.
This trial has a 5-week run-in/stabilisation period described as follows: subjects inadequately controlled [Asthma Control Questionnaire (ACQ-6) ≥ 1.5] on their current asthma treatment of inhaled corticosteroid (greater than fluticasone propionate 250 microgram per day or equivalent) plus LABA entered a 3-week run-in period of treatment with fluticasone propionate/salmeterol 250/50 microgram twice daily. Subjects who remained inadequately controlled (ACQ-6 ≥ 1.5) after the run-in period were transferred to fluticasone furoate/vilanterol (FF/VI) 100/25 microgram once daily for a 2-week stabilisation period. Across all treatment groups, baseline demographics were similar.
At screening, the mean prebronchodilator percent predicted FEV1 was 58.5% (SD: 12.8%); the mean percent reversibility was 29.9% (SD: 18.1%), with a mean absolute reversibility of 0.484 L (SD: 0.274 L), and the mean ACQ-6 score was 2.5 (SD: 0.6). During the 5-week run-in/stabilisation period, subjects had substantial improvements in both lung function (trough FEV1 improvement of 0.287 L) and asthma control (mean ACQ-6 score decreased by 0.6). Despite these improvements, a majority of subjects (93%) were not well controlled (mean score ACQ-6 of 1.9), demonstrating the need for additional therapy. At randomisation, the mean prebronchodilator percent predicted FEV1 was 68.2% (SD: 14.8%).
After the 5-week run-in/stabilisation period, eligible subjects were randomised to receive once-daily inhalations of FF/UMEC/VI 100/62.5/25 microgram (n = 406), FF/UMEC/VI 200/62.5/25 microgram (n = 408), FF/UMEC/VI 100/31.25/25 microgram (n = 405), FF/UMEC/VI 200/31.25/25 microgram (n = 404), FF/VI 100/25 microgram (n = 407), or FF/VI 200/25 microgram (n = 406).
While 4 doses of FF/UMEC/VI were studied in the trial, efficacy data results shown are for FF/UMEC/VI 100/62.5/25 microgram and FF/UMEC/VI 200/62.5/25 microgram, the recommended doses for the treatment of asthma. In the evaluation of efficacy, the non-lung function endpoint analyses included prespecified pooled comparisons of FF/UMEC/VI (100/62.5/25 and 200/62.5/25 microgram) with FF/VI (100/25 and 200/25 microgram).
The change from baseline in trough FEV1 at Week 24 (primary efficacy endpoint) showed statistically significant improvements in lung function for both FF/UMEC/VI 100/62.5/25 microgram and FF/UMEC/VI 200/62.5/25 microgram compared with FF/VI 100/25 microgram and FF/VI 200/25 microgram, respectively (see Table 6, Figures 5 and 6).
Moderate/severe asthma exacerbations were assessed over the 52-week treatment period (see Table 7). In the pooled analysis, the annualised rate of moderate/severe exacerbations was numerically lower with FF/UMEC/VI (100/62.5/25 and 200/62.5/25 microgram) compared with FF/VI (100/25 and 200/25 microgram) (13% reduction in rate; 95% CI: -5.2, 28.1). Descriptive analyses of unpooled treatment comparisons for the annualised rate of moderate/severe exacerbations are also provided.
In addition, severe asthma exacerbations were assessed. In a descriptive pooled analysis, a difference in the mean annualised rate of severe exacerbations was not observed for FF/UMEC/VI (100/62.5/25 and 200/62.5/25 microgram) compared with FF/VI (100/25 and 200/25 microgram) (2.6% reduction in rate; 95% CI: -26.2, 24.9).
The mean annualised rates of severe exacerbations were 0.41 and 0.23 for FF/UMEC/VI 100/62.5/25 microgram and FF/UMEC/VI 200/62.5/25 microgram, respectively. The mean annualised rates of severe exacerbations were 0.38 and 0.26 for FF/VI 100/25 microgram and FF/VI 200/25 microgram, respectively.
Patient symptoms and health-related quality of life were assessed using the ACQ (see Table 8). In a descriptive pooled analysis, the treatment difference for the ACQ-7 change from baseline at Week 24 for FF/UMEC/VI (100/62.5/25 and 200/62.5/25) compared with FF/VI (100/25 and 200/25) was -0.089 (-0.156, -0.023). The ACQ-7 responder rate was 63% for FF/UMEC/VI (100/62.5/25 and 200/62.5/25 microgram) compared with 55% for FF/VI (100/25 and 200/25 microgram) at Week 24 (OR: 1.43; 95% CI: 1.16, 1.76). Descriptive analyses of unpooled treatment comparisons are also provided.
The ACQ-5 (comprising the 5 questions on symptoms from ACQ-7) results at Week 24 were similar to the ACQ-7 results. In a pooled descriptive analysis, the treatment difference for the ACQ-5 change from baseline for FF/UME/VI (100/62.5/25 and 200/62.5/25) compared with FF/VI (100/25 and 200/25) was -0.043 (-0.121, 0.035). The ACQ-5 responder rate was 64% for FF/UMEC/VI (100/62.5/25 and 200/62.5/25 microgram) compared with 60% for FF/VI (100/25 and 200/25 microgram) (OR: 1.23; 95% CI: 1.00, 1.52) at Week 24.
In an unpooled descriptive analysis, the treatment difference for the ACQ-5 change from baseline at Week 24 for FF/UMEC/VI 100/62.5/25 compared with FF/VI 100/25 was -0.080 (-0.189, 0.030) and for FF/UMEC/VI 200/62.5/25 compared with FF/VI 200/25 was -0.006 (-0.116, 0.103). The ACQ-5 responder rate was 63% for FF/UMEC/VI 100/62.5/25 microgram compared with 58% for FF/VI 100/25 microgram (OR: 1.28; 95% CI: 0.96, 1.72) at Week 24. The ACQ-5 responder rate was 66% for FF/UMEC/VI 200/62.5/25 microgram compared with 62% for FF/VI 200/25 microgram (OR: 1.19, 95% CI: 0.88, 1.60) at Week 24.
COPD.

Study 1 (CTT116853, FULFIL).

The efficacy of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI 100/62.5/25 microgram) administered as a once-daily treatment in patients with a clinical diagnosis of COPD has been evaluated in one 24-week active-controlled study (compared to budesonide/formoterol [BUD/FOR]) with an extension up to 52 weeks in a subset of patients.
All patients were required to have a smoking history of at least 10 pack years; a post-salbutamol FEV1/ FVC ratio < 0.70; a clinical diagnosis of COPD, and a post-bronchodilator FEV1 of < 50% predicted normal or a post-bronchodilator FEV1 < 80% predicted normal and a history of ≥ 2 moderate exacerbations or one severe (hospitalised) exacerbation in the previous 12 months at screening. At screening, the mean post-bronchodilator FEV1 was 45.5% predicted, and the mean reversibility was 8.17%. Approximately 55% of patients had a history of ≥ 2 moderate or ≥ 1 severe COPD exacerbations in the 12 months prior to screening.
FF/UMEC/VI 100/62.5/25 microgram administered once daily demonstrated a statistically significant improvement in lung function (as defined by change from baseline trough FEV1 at Week 24; co-primary endpoint) compared with BUD/FOR 400/12 microgram administered twice-daily (see Table 9).
FF/UMEC/VI demonstrated a statistically significant improvement compared with BUD/FOR at Week 24 for Health Related Quality of Life (HRQoL) measured by the St George's Respiratory Questionnaire (SGRQ) total score (co-primary endpoint), SGRQ responder analysis, and also for respiratory symptoms measured using the Evaluating Respiratory Symptoms in COPD (E-RS: COPD) score and sub-scale scores over Weeks 21-24, and breathlessness measured using the Transitional Dyspnoea Index (TDI) focal score at Week 24 (see Table 9).
FF/UMEC/VI demonstrated a statistically significant reduction in the annual rate of moderate/severe exacerbations (i.e. requiring treatment with antibiotics or corticosteroids or hospitalisation; extrapolated from data up to Week 24) compared with BUD/FOR (see Table 9).
The lung function, HRQoL, symptoms and exacerbations outcomes up to 52 weeks of treatment in a subset of patients (n = 430) were consistent with the results up to 24 weeks.

Study 2 (CTT116855, IMPACT).

The long-term efficacy of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI 100/62.5/25 microgram) administered once daily in patients with COPD with a history of moderate or severe exacerbations within the prior 12 months has been evaluated in a 52-week, active-controlled study compared with the fixed-dose combination of fluticasone furoate/vilanterol (FF/VI 100/25 microgram) and umeclidinium/vilanterol (UMEC/VI 62.5/25 microgram) (randomisation 2:2:1). At screening, approximately 90% of patients were using medications to control COPD: 34% triple therapy (ICS + LABA + LAMA), 26% combined ICS and LABA, 8% combined LAMA and LABA, 7% LAMA and 2% LABA monotherapy.
Patients treated with FF/UMEC/VI demonstrated a statistically significant reduction in the annual rate of on-treatment moderate/severe exacerbations (primary endpoint) compared with FF/VI and compared with UMEC/VI. See Table 10 for efficacy endpoint results.
The effects on lung function (change from baseline trough FEV1) of FF/UMEC/VI compared with FF/VI and UMEC/VI for trough FEV1 were observed at all timepoints over the course of the 52-week study (see Figure 7).
Other supporting efficacy studies.

Umeclidinium with fluticasone furoate/vilanterol.

In two 12-week, placebo controlled studies (200109 and 200110), the addition of umeclidinium (62.5 microgram) to fluticasone furoate/vilanterol (FF/VI) (100/25 microgram) once daily in adult patients with a clinical diagnosis of COPD, resulted in statistically significant and clinically meaningful improvements in the primary endpoint of trough FEV1 at Day 85 compared with placebo plus FF/VI (124 mL [95% CI: 93, 154, p < 0.001] in Study 200109 and 122 mL [95% CI: 91, 152, p < 0.001] in Study 200110).

5.2 Pharmacokinetic Properties

When fluticasone furoate, umeclidinium (as bromide) and vilanterol (as trifenatate) were administered in combination by the inhaled route from a single inhaler in healthy subjects, the pharmacokinetics of each component were similar to those observed when each active substance was administered either as fluticasone furoate/vilanterol (FF/VI) combination, umeclidinium/vilanterol (UMEC/VI) combination or umeclidinium monotherapy.
Population pharmacokinetic (PK) analyses were conducted to assess the systemic exposure of fluticasone furoate, umeclidinium, and vilanterol in subjects with asthma. In these analyses, systemic drug levels (steady-state Cmax and AUC0-24) of fluticasone furoate and vilanterol following fluticasone furoate/umeclidinium/vilanterol (100/62.5/25 microgram and 200/62.5/25 microgram) in one inhaler (triple combination) were within the range of those observed following administration of the dual combination of FF/VI with the respective 100 microgram and 200 microgram FF doses; the systemic exposure of umeclidinium 62.5 microgram following fluticasone furoate/umeclidinium/vilanterol in one inhaler was within the range of those observed following administration of umeclidinium 62.5 microgram as monotherapy.
Population PK analyses for fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 microgram were conducted using a combined dataset from three, phase III studies in 821 COPD subjects. Based on data from this analysis and historical datasets, systemic drug levels (steady state Cmax and AUC0-24) of fluticasone furoate, umeclidinium (as bromide) and vilanterol (as trifenatate) following fluticasone furoate/umeclidinium/vilanterol in one inhaler (triple combination) were within the range of those observed following fluticasone furoate/vilanterol + umeclidinium as two inhalers, dual combinations (fluticasone furoate/vilanterol and umeclidinium/vilanterol) as well as individual single inhalers (fluticasone furoate, umeclidinium and vilanterol).

Absorption.

Fluticasone furoate.

Following inhaled administration of fluticasone furoate/umeclidinium/vilanterol in healthy subjects, fluticasone furoate Cmax occurred at 15 minutes. The absolute bioavailability of fluticasone furoate when administrated as fluticasone furoate/vilanterol by inhalation was on average 15.2%, primarily due to absorption of the inhaled portion of the dose delivered to the lung, with negligible contribution from oral absorption. Following repeat dosing of inhaled fluticasone furoate/vilanterol, steady state was achieved within 6 days with up to 1.6-fold accumulation.

Umeclidinium (as bromide).

Following inhaled administration of fluticasone furoate/umeclidinium/vilanterol in healthy subjects, umeclidinium Cmax occurred at 5 minutes. The absolute bioavailability of inhaled umeclidinium was on average 13%, with negligible contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 7 to 10 days with 1.5 to 2-fold accumulation.

Vilanterol (as trifenatate).

Following inhaled administration of fluticasone furoate/umeclidinium/vilanterol in healthy subjects, vilanterol Cmax occurred at 7 minutes. The absolute bioavailability of inhaled vilanterol was on average 27%, with negligible contribution from oral absorption. Following repeat dosing of inhaled fluticasone furoate/vilanterol, steady state was achieved within 6 days with up to 1.5-fold accumulation.

Distribution.

Fluticasone furoate.

Following intravenous dosing, fluticasone furoate is extensively distributed with an average volume of distribution at steady state of 661 L.
Fluticasone furoate has a low association with red blood cells. In vitro plasma protein binding in human plasma of fluticasone furoate was high, on average > 99.6%. There was no decrease in the extent of in vitro plasma protein binding in subjects with renal or hepatic impairment.
Fluticasone furoate is a substrate for P-glycoprotein (P-gp), however, concomitant administration of fluticasone furoate with P-gp inhibitors is considered unlikely to alter fluticasone furoate systemic exposure. Clinical pharmacology studies with selective P-gp inhibitors and fluticasone furoate have not been conducted.

Umeclidinium (as bromide).

Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L. In vitro plasma protein binding in human plasma was on average 89%.

Vilanterol (as trifenatate).

Following intravenous administration to healthy volunteers, the mean volume of distribution at steady state was 165 L. In vitro plasma protein binding in human plasma was on average 94%.

Metabolism.

Fluticasone furoate.

Based on in vitro data, the major routes of metabolism of fluticasone furoate in humans are mediated primarily by CYP3A4.
Fluticasone furoate is primarily metabolised through hydrolysis of the S-fluoromethyl carbothioate group to metabolites with significantly reduced corticosteroid activity.
A repeat-dose CYP3A4 drug interaction study was performed in healthy subjects with the fluticasone furoate/vilanterol combination (200/25 microgram) and the strong CYP3A4 inhibitor ketoconazole (400 milligram). Co-administration increased mean fluticasone furoate AUC(0-24) and Cmax by 36% and 33%, respectively. The increase in fluticasone furoate exposure was associated with a 27% reduction in 0-24 hour weighted mean serum cortisol.

Umeclidinium (as bromide).

In vitro studies showed that umeclidinium is metabolised principally by CYP2D6 and is a substrate for the P-gp transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.

Vilanterol (as trifenatate).

In vitro studies showed that vilanterol is metabolised principally via CYP3A4 and is a substrate for the P-gp transporter. The primary metabolic routes are O-dealkylation to a range of metabolites with significantly reduced beta1- and beta2-agonist activity. Plasma metabolic profiles following oral administration of vilanterol in a human radiolabel study were consistent with high first-pass metabolism. Systemic exposure to the metabolites is low.

Excretion.

Fluticasone furoate.

Following intravenous administration, the elimination phase half-life averaged 15.1 hours. Plasma clearance following intravenous administration was 65.4 L/hour. Urinary excretion accounted for approximately 2% of the intravenously administered dose.
Following oral administration, fluticasone furoate was eliminated in humans mainly by metabolism with metabolites being excreted almost exclusively in faeces. Less than 1% of the recovered radioactive dose was eliminated in the urine. The apparent plasma elimination half-life following inhaled administration of fluticasone furoate was, on average, 24 hours.

Umeclidinium (as bromide).

Plasma clearance following intravenous administration was 151 L/hour. Following intravenous administration, approximately 58% of the administered radiolabelled dose (or 73% of the recovered radioactivity) was excreted in faeces by 192 hours post-dose. Urinary elimination accounted for 22% of the administered radiolabelled dose by 168 hours (27% of recovered radioactivity). The excretion of the drug-related material in the faeces following intravenous dosing indicated secretion into the bile. Following oral administration to healthy male subjects, total radioactivity was excreted primarily in faeces (92% of the administered radiolabelled dose or 99% of the recovered radioactivity) by 168 hours post-dose. Less than 1% of the orally administered dose (1% of recovered radioactivity) was excreted in urine, suggesting negligible absorption following oral administration. Umeclidinium plasma elimination half-life following inhaled dosing for 10 days averaged 19 hours, with 3% to 4% drug excreted unchanged in urine at steady-state.

Vilanterol (as trifenatate).

Plasma clearance of vilanterol following intravenous administration was 108 L/hour. Following oral administration of radiolabelled vilanterol, mass balance showed 70% of the radiolabel in urine and 30% in faeces. Primary elimination of vilanterol was by metabolism followed by excretion of metabolites in urine and faeces. Vilanterol plasma elimination half-life following inhaled dosing for 10 days averaged 11 hours.

Special patient populations.

In the asthma population pharmacokinetic analyses (1,265 subjects for fluticasone furoate; 1,263 subjects for vilanterol; 634 subjects for umeclidinium), the impact of demographic covariates (race/ethnicity, age, gender, weight) on the pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol was evaluated. In a COPD population pharmacokinetic analysis (n = 821), the impact of demographic covariates (race/ethnicity, age, gender, weight) on the pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol was evaluated. Renal and hepatic impairment were assessed in separate studies.

Race.

No clinically relevant differences requiring dose adjustment in asthma or COPD based on race were observed in fluticasone furoate, umeclidinium or vilanterol systemic exposure.
In 92 East Asian subjects with asthma (Japanese, East Asian and Southeast Asian heritage) who provided FF/UMEC/VI (100/62.5/25 microgram and 200/62.5/25 microgram) population pharmacokinetic data, estimates of vilanterol Cmax at steady state was approximately 3-fold higher than non-East Asian subjects. There was no effect of race on pharmacokinetics of fluticasone furoate or umeclidinium in subjects with asthma.
In 113 East Asian subjects with COPD (Japanese and East Asian heritage) who received FF/UMEC/VI 100/62.5/25 microgram from a single inhaler (27% subjects), estimates of fluticasone furoate AUC(0-24) were on average 30% higher compared with Caucasian subjects. However, these higher systemic exposures are not expected to have a clinically relevant effect on 24 hour serum or urinary cortisol excretion. There was no effect of race on pharmacokinetics of umeclidinium or vilanterol in subjects with COPD.

Elderly.

No clinically relevant effects requiring dose adjustment were observed for subjects with asthma or COPD.

Renal impairment.

Fluticasone furoate/umeclidinium/vilanterol has not been evaluated in subjects with renal impairment. However, such studies have been conducted with fluticasone furoate/vilanterol and umeclidinium/vilanterol.
A clinical pharmacology study of fluticasone furoate/vilanterol showed that severe renal impairment (creatinine clearance < 30 mL/min) did not result in significantly greater exposure to fluticasone furoate or vilanterol or more marked corticosteroid or beta2-agonist systemic effects compared with healthy subjects.
A study in subjects with severe renal impairment administered with umeclidinium/vilanterol showed no evidence of an increase in systemic exposure to either umeclidinium or vilanterol (Cmax and AUC). In vitro protein binding studies between subjects with severe renal impairment and healthy volunteers were conducted, and no clinically significant evidence of altered protein binding was seen.
The effects of haemodialysis have not been studied.

Hepatic impairment.

Fluticasone furoate/umeclidinium/vilanterol has not been evaluated in subjects with hepatic impairment. However, such studies have been conducted with fluticasone furoate/vilanterol and umeclidinium/vilanterol.
Following repeat dosing of fluticasone furoate/vilanterol for 7 days, there was an increase in fluticasone furoate systemic exposure (up to three-fold as measured by AUC(0-24)) in subjects with hepatic impairment (Child-Pugh A, B or C) compared with healthy subjects. No clinically relevant effects on weighted mean serum cortisol were observed in subjects with mild hepatic impairment (Child-Pugh A). The increase in fluticasone furoate systemic exposure in subjects with moderate hepatic impairment (Child-Pugh B) following repeat-dose administration (fluticasone furoate/vilanterol 200/25 microgram) was associated with an average 34% reduction in serum cortisol compared with healthy subjects. In subjects with severe hepatic impairment (Child-Pugh C) that received fluticasone furoate/vilanterol 100/12.5 microgram, there was no reduction in serum cortisol (10% increase in serum cortisol). For patients with moderate or severe hepatic impairment the maximum dose is 100/62.5/25 microgram (see Section 4.2 Dose and Method of Administration).
Following repeat dosing of fluticasone furoate/vilanterol for 7 days, there was no significant increase in systemic exposure to vilanterol (Cmax and AUC) in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh A, B or C).
There were no clinically relevant effects of the fluticasone furoate/vilanterol combination on beta-adrenergic systemic effects (heart rate or serum potassium) in subjects with mild or moderate hepatic impairment (vilanterol, 25 microgram) or with severe hepatic impairment (vilanterol, 12.5 microgram) compared with healthy subjects.
Subjects with moderate hepatic impairment showed no evidence of an increase in systemic exposure to either umeclidinium or vilanterol (Cmax and AUC), and no evidence of altered protein binding by umeclidinium or decreased protein binding by vilanterol between subjects with moderate hepatic impairment and healthy volunteers was observed in vitro.
Umeclidinium has not been evaluated in subjects with severe hepatic impairment.

Other patient characteristics.

No dose adjustment is required for fluticasone furoate, umeclidinium or vilanterol based on the effect of gender, weight or body mass index.
In terms of other patient characteristics, a study in CYP2D6-poor metabolisers showed no evidence of a clinically significant effect of CYP2D6 genetic polymorphism on systemic exposure to umeclidinium.

5.3 Preclinical Safety Data

Genotoxicity.

Fluticasone furoate was not genotoxic in a standard battery of studies, comprising bacterial mutation (Ames) assays, mouse lymphoma assay and rat bone marrow micronucleus tests.
Umeclidinium was not genotoxic in a standard battery of studies, comprising bacterial mutation assays, the mouse lymphoma tk assay and the rat bone marrow micronucleus test.
Vilanterol was negative in a complete battery of in vitro (Ames, UDS, SHE cell) assays and in vivo (rat bone marrow micronucleus) assays and equivocal in the mouse lymphoma assay. The weight of evidence suggests that vilanterol does not pose a genotoxic risk.

Carcinogenicity.

No carcinogenicity studies were performed with the fluticasone furoate/umeclidinium/vilanterol combination.
Fluticasone furoate was not carcinogenic in lifetime inhalation studies in rats or mice at exposures of 0.6- or 1.3-fold, respectively, than in humans at 184 microgram delivered dose/day, based on AUC.
Umeclidinium was not carcinogenic in 2-year inhalation studies in mice or rats at doses yielding systemic exposure levels (plasma AUC) ≥ 20- or 17-fold the human clinical exposure of umeclidinium at 55 microgram delivered dose/day in the respective species.
Proliferative effects in the female rat and mouse reproductive tract and rat pituitary gland were observed in lifetime inhalation studies with vilanterol, consistent with findings for other beta2-agonists. There was no increase in tumour incidence in rats or mice at exposures 0.9 or 22-fold, respectively, the human clinical exposure of vilanterol at 22 microgram delivered dose/day, based on AUC. These findings are not considered to indicate that vilanterol poses a carcinogenic hazard to patients.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate (which contains milk protein), magnesium stearate.

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.
Following removal from the tray, the product may be stored for a maximum period of 1 month.
Write the date that the inhaler should be discarded on the label in the space provided. The date should be added as soon as the inhaler has been removed from the tray.

6.4 Special Precautions for Storage

Store below 30°C.
If stored in the refrigerator, allow the inhaler to return to room temperature for at least 1 hour before use.

6.5 Nature and Contents of Container

Trelegy Ellipta is a moulded plastic dry powder inhaler with a light grey body, a beige mouthpiece cover and a dose counter, packed in a foil tray containing a desiccant sachet. The tray is sealed with a peelable foil lid.
The inhaler contains two strips of either 14 or 30 regularly distributed blisters.
Not all pack sizes and strengths may be distributed in Australia.

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

Fluticasone furoate is practically insoluble or insoluble in water, and slightly soluble in acetone, dimethylsulphoxide and ethanol.
Umeclidinium (as bromide) is slightly soluble in water and slightly soluble in methanol, ethanol, acetonitrile and propan-1-ol.
Vilanterol (as trifenatate) is practically insoluble or insoluble in water and slightly soluble in methanol, ethanol, acetonitrile and propan-2-ol.

Chemical structure.

Fluticasone furoate.

Chemical name: androsta-1,4-diene-17-carbothioic acid, 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-, S-(fluoromethyl) ester, (6α,11β,16α,17α)- (9Cl).
Molecular formula: C27H29F3O6S.
Structure:

Umeclidinium (as bromide).

Chemical name: 1-Azoniabicyclo[2.2.2]octane, 4-(hydroxydiphenylmethyl)-1-[2-(phenylmethoxy) ethyl]-, bromide (1:1).
Molecular formula: C29H34BrNO2.
Structure:

Vilanterol (as trifenatate).

Chemical name: benzeneacetic acid, α,α-diphenyl-, compd. with (α1R)-α1-[[[6-[2-[(2,6-dichlorophenyl)methoxy]ethoxy] hexyl]amino]methyl]-4-hydroxy-1,3-benzene dimethanol (1:1).
Molecular formula: C24H33Cl2NO5.C20H16O2.
Structure:

CAS number.

Fluticasone furoate: 397864-44-7.
Umeclidinium (as bromide): 869113-09-7.
Vilanterol (as trifenatate): 503070-58-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes