Consumer medicine information

Breo Ellipta

Fluticasone furoate; Vilanterol

BRAND INFORMATION

Brand name

Breo Ellipta

Active ingredient

Fluticasone furoate; Vilanterol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

Please read this leaflet carefully before you start using BREO ELLIPTA.

This leaflet answers some common questions about BREO ELLIPTA.

It does not contain all the available information.

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

All medicines have risks and benefits. Your doctor has weighed the risks of you taking BREO ELLIPTA against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What BREO ELLIPTA is used for

BREO ELLIPTA is used to treat asthma and chronic obstructive pulmonary disease (COPD). To use BREO ELLIPTA, you breathe it into your lungs through your mouth using the ELLIPTA inhaler.

Asthma is when the muscles surrounding the smaller airways become tight (bronchoconstriction), swollen and irritated (inflammation). Symptoms come and go and include shortness of breath, wheezing, chest tightness and cough.

COPD is a long-term condition that slowly gets worse. Symptoms include shortness of breath, cough, chest discomfort and coughing up mucus. BREO ELLIPTA has been shown to reduce flare-ups of COPD symptoms.

BREO ELLIPTA contains two active ingredients: fluticasone furoate and vilanterol trifenatate.

Fluticasone furoate belongs to a group of medicines called corticosteroids, often simply called steroids. 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. Corticosteroids also help to prevent attacks of asthma.

Vilanterol trifenatate belongs to a group of medicines called bronchodilators. It relaxes 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 taken regularly, it helps the small air passages to remain open.

When you take these two medicines together regularly, they will help to control your breathing difficulties.

BREO 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).

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 doctor's prescription.

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

BREO ELLIPTA should not be used in children under the age of 12 years.

Before you use BREO ELLIPTA

Bronchodilators similar to vilanterol (one of the ingredients in BREO ELLIPTA) as a class of medicines can very rarely be associated with an increased risk of potentially life-threatening worsening of your asthma. However, not treating your asthma sufficiently can also similarly put you at risk. Your doctor has weighed any risks of you using BREO ELLIPTA against the benefits they expect it will have for you. You can talk to your doctor about the risks and benefits of using this medicine.

When you must not use it

Don't use BREO ELLIPTA

  • if you are allergic (hypersensitive) to lactose or milk protein
  • if you are allergic (hypersensitive) to fluticasone furoate, vilanterol or any other ingredients of BREO ELLIPTA (listed at the end of this leaflet).

If you think either of these applies to you, don't use BREO ELLIPTA until you have checked with your doctor.

Some of the symptoms of an allergic reaction may include:

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

BREO ELLIPTA contains lactose.

If you have been diagnosed with an intolerance to some sugars, or to milk protein, talk to your doctor before you use BREO ELLIPTA.

BREO ELLIPTA is not usually recommended for use during pregnancy.

If you are pregnant, if you think you may be pregnant don't use BREO ELLIPTA without asking your doctor. Your doctor will consider the benefit to you and the risk to your baby of taking BREO ELLIPTA while you are pregnant.

If you are breast-feeding, check with your doctor before you take BREO ELLIPTA. It is not known whether the ingredients of BREO ELLIPTA can pass into breast milk.

Do not give this medicine to a child under the age of 12 years. Safety and effectiveness in children younger than 12 years have not been established.

BREO ELLIPTA 200/25 is not recommended in asthma patients aged 75 years and older.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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

Before you start to use it

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 or pharmacist if you have any questions about your Action Plan.

Talk to your doctor before you use BREO ELLIPTA if you:

  • 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 BREO ELLIPTA (100/25 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 or have ever been treated for tuberculosis (TB) or pneumonia
  • have eye problems such as glaucoma or cataracts
  • have weak bones (osteoporosis)
  • have diabetes
  • have problems with your thyroid
  • have seizures
  • have any long-standing or untreated infections or have recently been exposed to chickenpox or measles or been around anyone who has chickenpox or measles
  • have any other medical conditions
  • if you have a problem with your immune system

Check with your doctor before you use BREO ELLIPTA if you think any of these apply to you.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

Taking other medicines

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

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

Some medicines may affect how BREO ELLIPTA works, or make it more likely that you'll have side effects. These include:

  • ketoconazole, to treat fungal infections.
  • ritonavir, to treat viral infections
  • medicines to treat depression or mood/mental disorders (such as monoamine oxidase inhibitors or tricyclics antidepressants).

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

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

How to use BREO ELLIPTA

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

If you do not understand the instructions in the user leaflet, ask your doctor or pharmacist for help.

How much to use

Always use BREO ELLIPTA exactly as your doctor has told you. Check with your doctor, nurse or pharmacist if you're not sure.

Asthma
The usual dose of BREO ELLIPTA for asthma is one inhalation 100 micrograms of fluticasone furoate and 25 micrograms of vilanterol once daily at the same time each day.

If you have severe asthma, your doctor may decide that you should use one inhalation of the higher strength BREO ELLIPTA inhaler (200 micrograms fluticasone furoate and 25 micrograms of vilanterol).

Your doctor will assess your asthma at regular intervals to ensure that you are receiving the dose most suitable to the severity of your asthma.

COPD
The dose of BREO ELLIPTA for COPD is one inhalation 100 micrograms of fluticasone furoate and 25 micrograms of vilanterol once daily at the same time each day.

The higher strength of BREO ELLIPTA is not suitable for the treatment of COPD.

How to use the inhaler

The full instructions for using BREO ELLIPTA are given on a leaflet inside the pack.

BREO ELLIPTA is ready to use straight away. No preparation or checks of the inhaler are required.

Do not open BREO ELLIPTA until you are ready to take a dose.

After using BREO ELLIPTA, you may clean the mouthpiece, using a dry tissue, before you close the cover. Do not immerse BREO ELLIPTA in water.

When to use it

Use BREO ELLIPTA regularly. It is very important that you use BREO ELLIPTA every day, as instructed by your doctor. This will help to keep you free of symptoms throughout the day and night.

If you feel you are getting breathless or wheezy more often than normal, or if you are using your quick-acting inhaler more than usual, see your doctor.

How long to use it

Don't stop BREO ELLIPTA without medical advice.

Use BREO ELLIPTA for as long as your doctor recommends. It will only be effective as long as you are using it. Don't stop unless your doctor advises you to, even if you feel better.

If you forget to take it

If it is almost time for your next dose, 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.

Don't take an extra dose to make up for a missed dose.

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

If you become wheezy or breathless, or develop any other symptoms of an asthma attack, use your quick-acting inhaler (e.g. VENTOLIN), then seek medical advice.

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

If you take too much (overdose)

In Australia, immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, if you think that you or anyone else may have taken too much BREO ELLIPTA. Do this even if there are no signs of discomfort or poisoning.

If you accidentally take a larger dose of BREO ELLIPTA than your doctor has instructed, you may notice that your heart is beating faster than usual, you feel shaky or have a headache.

If you have used larger doses than instructed for a long period of time, it is particularly important that you ask your doctor or pharmacist for advice.This is because larger doses of BREO ELLIPTA may reduce the amount of steroid hormones produced naturally by your body.

While you are using BREO ELLIPTA

Things you must do

Contact your doctor if you experience a change in your vision.

Contact your doctor if you experience increased thirst, frequent urination or unexplained tiredness (signs of high blood sugar).

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

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking BREO ELLIPTA.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

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

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

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not take BREO ELLIPTA to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Do not take any other medicines for your breathing problems without checking with your doctor.

Things to be careful of

This medicine is not expected to affect your ability to drive a car or operate machinery. It is prudent to be careful with driving or operating machinery until you know how BREO ELLIPTA affects you.

Side effects

Like all medicines, BREO ELLIPTA can cause side effects, although not everybody gets them. To reduce the chance of side effects, your doctor will prescribe the lowest effective dose of BREO ELLIPTA to control your asthma or COPD.

If your breathing or wheezing gets worse straight after using BREO ELLIPTA, stop using it and get medical help immediately.

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

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

Very Common side effects

These may affect more than 1 in 10 people:

  • headache
  • common cold

Common side effects

These may affect up to 1 in 10 people:

  • sore, raised patches in the mouth or throat caused by a fungal infection (candidiasis). Rinsing your mouth out with water immediately after using BREO ELLIPTA may help stop this side effect developing
  • infection of the lungs (pneumonia).
    You must tell your doctor if you have any of the following symptoms while taking BREO ELLIPTA: fever, chills, increased sputum production, change in sputum colour, increased cough or increased breathing difficulties.
  • inflammation of the lungs (bronchitis)
  • infection of the nose sinuses or throat
  • flu (influenza)
  • pain and irritation in the back of the mouth and throat
  • inflammation of the sinuses
  • itchy, runny or blocked nose
  • cough
  • voice disorders
  • weakening of the bones, leading to risk of fractures
  • stomach pain
  • high temperature (fever)
  • joint and back pain
  • muscle spasms

Uncommon side effects

These may affect up to 1 in 100 people:

  • irregular heartbeat
  • increase in blood sugar (hyperglycaemia). This may lead to increased thirst, frequent urination or unexplained tiredness.

If you think you are having an allergic reaction to BREO ELLIPTA, stop using this medicine and tell your doctor immediately or go the accident and emergency department at your nearest hospital. Symptoms of an allergic reaction usually include some or all of the following:

  • wheezing
  • swelling of the lips/mouth, tongue or throat
  • difficulty in breathing
  • hay fever
  • lumpy rash ("hives")
  • fainting

It is possible that some people particularly those taking higher doses of BREO ELLIPTA for a long time, may rarely suffer from the following side effects:

  • Rounded face
  • Loss of bone density
  • Eye problems (e.g. cataract, glaucoma)
  • Slowing of growth in children. It is unclear what, if any, difference this makes to a child's final height
  • Immediate breathing difficulties and wheezing.

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

After using BREO ELLIPTA

Storage

Do not use BREO ELLIPTA after the expiry date shown on the pack.

Store in the original package container in order to protect from moisture and do not open the foil lid until ready to inhale for the first time.

Safely throw away BREO 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.

Keep your inhaler in cool dry place where the temperature stays below 30°C.

If you store in a refrigerator allow the inhaler to return to room temperature for at least an hour before use.

Do not store BREO ELLIPTA or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

BREO ELLIPTA is inhaled through the mouth using the ELLIPTA device. The active substances are in separate blisters in powder form inside the device. There are either 14 or 30 blisters on each strip, and so each device contains either 14 or 30 doses depending on which pack size you have been given.

The ELLIPTA device itself is a plastic inhaler with a light grey body, a pale blue mouthpiece cover and a dose counter. It is packaged in a foil laminate tray with a peelable foil lid. The tray contains a desiccant sachet, to reduce the moisture in the packaging. Once you have opened the lid of the tray, throw the desiccant away - do not open, eat or inhale it.

Ingredients

The active ingredients in BREO ELLIPTA are fluticasone furoate and vilanterol (as trifenatate).

Each dose contains 100 or 200 micrograms of the active ingredient fluticasone furoate. Each dose also contains 25 micrograms of the active ingredient vilanterol. The amount depends on which strength of BREO ELLIPTA you have been given.

BREO ELLIPTA also contains the inactive ingredients:

  • lactose monohydrate
  • magnesium stearate

Supplier

Your BREO ELLIPTA is supplied by:

GlaxoSmithKline Australia Pty Ltd
Level 4, 436 Johnston Street
Abbotsford Victoria 3067
Australia.

Where to go for further information

Pharmaceutical companies are not in a position to give people an individual diagnosis or medical advice. Your doctor or pharmacist is the best person to give you advice on the treatment of your condition. You may also be able to find general information about your disease and its treatment from patient information groups and books, for example in public libraries.

This leaflet was prepared on 11 Sep 2018.

The information provided applies only to: BREO ELLIPTA.

BREO ELLIPTA 100/25mcg: AUSTR 199748

BREO ELLIPTA 200/25mcg: AUSTR 199747

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

© 2018 GSK group of companies or its licensor.

Version 8.0

Published by MIMS January 2019

BRAND INFORMATION

Brand name

Breo Ellipta

Active ingredient

Fluticasone furoate; Vilanterol

Schedule

S4

 

1 Name of Medicine

Fluticasone furoate/ vilanterol trifenatate.

6.7 Physicochemical Properties

Fluticasone furoate is practically insoluble or insoluble in water, and slightly soluble in acetone, dimethylsulphoxide and ethanol.
Vilanterol trifenatate is practically insoluble or insoluble in water and slightly soluble in methanol, ethanol, acetonitrile and propan-2-ol.
See Table 10.

Chemical structure.


CAS number.

Fluticasone furoate: 397864-44-7; Vilanterol trifenatate: 503070-58-4.

2 Qualitative and Quantitative Composition

Breo Ellipta 100/25.

Each foil strip contains regularly distributed blisters with one strip containing a powder formulation of 100 micrograms of fluticasone furoate and the other strip containing 25 micrograms of vilanterol (as trifenatate). Each delivered dose (the dose leaving the mouthpiece) contains of 92 micrograms of fluticasone furoate and 22 micrograms of vilanterol (as trifenatate).

Breo Ellipta 200/25.

Each foil strip contains regularly distributed blisters with one strip containing a powder formulation of 200 micrograms of fluticasone furoate and the other strip containing 25 micrograms of vilanterol (as trifenatate). Each delivered dose (the dose leaving the mouthpiece) contains of 184 micrograms of fluticasone furoate and 22 micrograms of vilanterol (as trifenatate).

Excipients with known effect.

Breo Ellipta contains the excipient 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 pale blue mouthpiece cover and a dose counter.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fluticasone furoate and vilanterol represent two classes of medications (a synthetic corticosteroid and a selective, long acting beta2-receptor agonist).

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).

Vilanterol trifenatate.

Vilanterol trifenatate is a selective long acting, beta2-adrenergic agonist (LABA).
The pharmacologic effects of beta2-adrenoceptor agonist drugs, including vilanterol trifenatate, are at least in part attributable to stimulation of intracellular adenylate cyclase, the enzyme that catalyzes 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.
Molecular interactions occur between corticosteroids and LABAs, whereby steroids activate the beta2-receptor gene, increasing receptor number and sensitivity; and LABAs prime the glucocorticoid receptor for steroid-dependent activation and enhance cell nuclear translocation. These synergistic interactions are reflected in enhanced anti-inflammatory activity, which has been demonstrated in vitro and in vivo in a range of inflammatory cells relevant to the pathophysiology of both asthma and COPD. In peripheral blood mononuclear cells from subjects with COPD, a larger anti-inflammatory effect was seen in the presence of the combination of fluticasone furoate/vilanterol compared with fluticasone furoate alone at concentrations achieved with clinical doses.

Clinical trials.

Asthma.

The safety and efficacy of fluticasone furoate (FF) and vilanterol (VI) in the treatment of asthma has been evaluated in 3 randomised, double blind clinical trials of between 12 to 76 weeks in duration (HZA106827, HZA106829 and HZA106837) involving 3,210 patients 12 years of age and older with persistent asthma.
All subjects were using an ICS (inhaled corticosteroid) with or without LABA for at least 12 weeks prior to visit 1. In HZA106837 all patients had at least one exacerbation that required treatment with oral corticosteroids in the year prior to visit 1. HZA106827 was 12 weeks in duration and evaluated the efficacy of fluticasone furoate/ vilanterol 100 microgram/25 microgram [n = 201] and FF (fluticasone furoate) 100 microgram [n = 205] compared with placebo [n = 203], all administered once daily. HZA106829 was 24 weeks in duration and evaluated the efficacy of fluticasone furoate/ vilanterol 200 microgram/25 microgram [n = 197] and FF 200 microgram [n = 194]) both administered once daily compared with fluticasone propionate (FP) 500 microgram twice daily [n = 195].
In HZA106827/ HZA106829 the coprimary efficacy endpoints were change from baseline in clinic visit trough (pre-bronchodilator and predose) FEV1 at the end of the treatment period in all subjects and weighted mean serial FEV1 over 0-24 hours postdose calculated in a subset of subjects at the end of the treatment period. Change from baseline in the percentage of rescue free 24 hour periods during treatment was a powered secondary endpoint. Results for the primary and key secondary endpoints in these studies are described in Table 6.
In study HZA106829, FF 200 once daily was noninferior to FP 500 twice daily for the primary endpoint of trough FEV1 using a predefined noninferiority margin of -125 mL (treatment difference of 18 mL [95% CI: -66, 102]).
HZA106837 was of variable treatment duration (from a minimum of 24 weeks to a maximum of 76 weeks with the majority of patients treated for at least 52 weeks). In HZA106837 patients were randomised to receive either fluticasone furoate/ vilanterol 100 microgram/25 microgram [n = 1009] or FF 100 microgram [n = 1010] both administered once daily. In HZA106837 the primary endpoint was the time to first severe asthma exacerbation. A severe asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. Adjusted mean change from baseline in trough FEV1 was also evaluated as a secondary endpoint.
In HZA106837 the risk of experiencing a severe asthma exacerbation in patients receiving fluticasone furoate/ vilanterol 100 microgram/25 microgram was reduced by 20% compared with FF 100 microgram alone (hazard ratio 0.795, p = 0.036 95% CI (0.642, 0.985)). The rate of severe asthma exacerbations per patient per year was 0.19 in the FF 100 group (approximately 1 in every 5 years) and 0.14 in the fluticasone furoate/ vilanterol 100 microgram/25 microgram group (approximately 1 in every 7 years). The ratio of the exacerbation rate for fluticasone furoate/ vilanterol 100 microgram/25 microgram versus FF 100 was 0.755 (95% CI 0.603, 0.945). This represents a 25% reduction in the rate of severe asthma exacerbations for subjects treated with fluticasone furoate/ vilanterol 100 microgram/25 microgram compared with FF 100 (p = 0.014). The 24 hour bronchodilator effect of fluticasone furoate/ vilanterol was maintained throughout a one year treatment period with no evidence of loss in efficacy (no tachyphylaxis). Fluticasone furoate/ vilanterol 100 microgram/25 microgram consistently demonstrated 83 mL to 95 mL improvements in trough FEV1 at weeks 12, 36 and 52 and endpoint compared with FF 100 microgram (p < 0.001 95% CI 52, 126 mL at endpoint). Forty four percent of patients in the fluticasone furoate/ vilanterol 100 microgram/25 group were well controlled (ACQ7 ≤ 0.75) at end of treatment compared to 36% of subjects in the FF 100 microgram group (p < 0.001 95% CI 1.23, 1.82).

Studies versus salmeterol/ fluticasone propionate combinations.

In a 24 week study (HZA113091) in adult and adolescent patients with persistent asthma both fluticasone furoate/ vilanterol 100 microgram/25 microgram given once daily in the evening and FP/salmeterol 250/50 microgram given twice daily demonstrated improvements from baseline in lung function. Adjusted mean treatment increases from baseline in weighted mean 0-24 hours FEV1 of 341 mL (fluticasone furoate/ vilanterol) and 377 mL (FP/salmeterol) demonstrated an overall improvement in lung function over 24 hours for both treatments. The adjusted mean treatment difference of 37 mL between the groups was not statistically significant (p = 0.162).

Fluticasone furoate monotherapy.

A 24 week randomised, double blind placebo controlled study (FFA112059) evaluated the safety and efficacy of FF 100 microgram once daily [n = 114] and FP 250 microgram twice daily [n = 114] versus placebo [n = 115] in adult and adolescent patients with persistent asthma. All subjects had to have been on a stable dose of an ICS for at least 4 weeks prior to visit 1 (screening visit) and the use of LABAs was not permitted within 4 weeks of visit 1. The primary efficacy endpoint was change from baseline in clinic visit trough (pre-bronchodilator and predose) FEV1 at the end of the treatment period. Change from baseline in the percentage of rescue free 24 hour periods during the 24 week treatment period was a powered secondary. At the 24 week time point FF 100 and FP increased trough FEV1 by 146 mL (95% CI 36, 257 mL, p = 0.009) and 145 mL (95% CI 33, 257 mL, p = 0.011) respectively compared to placebo. FF and FP both increased the percentage of 24 hour rescue free periods by 14.8% (95% CI 6.9, 22.7, p < 0.001) and 17.9% (95% CI 10.0, 25.7, p < 0.001) respectively versus placebo.

Allergen challenge study.

The bronchoprotective effect of fluticasone furoate/ vilanterol 100 microgram/25 microgram on the early and late asthmatic response to inhaled allergen was evaluated in a repeat dose, placebo controlled four way crossover study (HZA113126) in patients with mild asthma. Patients were randomized to receive fluticasone furoate/ vilanterol 100/25 microgram, FF 100 microgram, VI (vilanterol) 25 microgram or placebo once daily for 21 days followed by challenge with allergen 1 hour after the final dose. The allergen was house dust mite, cat dander, or birch pollen; the selection was based on individual screening tests. Serial FEV1 measurements were compared with pre-allergen challenge values taken after saline inhalation (baseline). Overall, the greatest effects on the early asthmatic response were seen with fluticasone furoate/ vilanterol 100 microgram/25 microgram compared with FF 100 microgram or vilanterol 25 microgram alone. Both fluticasone furoate/ vilanterol (100 microgram/25 microgram) and FF 100 microgram virtually abolished the late asthmatic response compared with vilanterol alone. Fluticasone furoate/ vilanterol 100/25 microgram provided significantly greater protection against allergen induced bronchial hyperreactivity compared with monotherapies FF and VI as assessed on day 22 by methacholine challenge.

Chronic obstructive pulmonary disease.

The COPD clinical development programme included a 12-week (HZC113107), two 6-month (HZC112206, HZC112207), two one-year randomised controlled studies (HZC102970, HZC102871) and one long-term study (SUMMIT) in patients with a clinical diagnosis of COPD. These studies included measures of lung function, dyspnoea and moderate and severe exacerbations.

Six month studies.

HZC112206 and HZC112207 were 24 week randomised, double blind, placebo controlled, parallel group studies comparing the effect of the combination to vilanterol and FF alone and placebo. HZC112206 evaluated the efficacy of fluticasone furoate/ vilanterol 50 microgram/25 microgram [n = 206] and fluticasone furoate/ vilanterol 100 microgram/25 microgram [n = 206] compared with FF 100 microgram [n = 206], vilanterol 25 microgram [n = 205] and placebo (n = 207), all administered once daily. HZC112207 evaluated the efficacy of fluticasone furoate/ vilanterol 100 microgram/25 microgram [n = 204] and fluticasone furoate/ vilanterol 200 microgram/25 microgram [n = 205] compared with FF 100 microgram [n = 204], 200 microgram [n = 203] and vilanterol 25 microgram [n = 203] and placebo [n = 205], all administered once daily.
All patients were required to have a smoking history of at least 10 pack years; a post-salbutamol FEV1/FVC ratio less than or equal to 0.70; post-salbutamol FEV1 less than or equal to 70% predicted and have a modified Medical Research Council (mMRC) dyspnea score ≥ 2 (scale 0-4) at screening. At screening, the mean pre-bronchodilator FEV1 was 42.6% and 43.6% predicted, and the mean reversibility was 15.9% and 12.0% in HZC112206 and HZC112207, respectively. The coprimary endpoints in both studies were weighted mean FEV1 from zero to 4 hours postdose at day 168 and change from baseline in predose trough FEV1 at day 169.
In an integrated analysis of both studies, fluticasone furoate/ vilanterol 100 microgram/25 microgram showed clinically meaningful improvements in lung function. At day 169 fluticasone furoate/ vilanterol 100 microgram/25 microgram and vilanterol increased adjusted mean trough FEV1 by 129 mL (95% CI: 91, 167 mL, p < 0.001) and 83 mL (95% CI: 46, 121 mL, p < 0.001) respectively compared to placebo. Fluticasone furoate/ vilanterol 100 microgram/25 microgram increased trough FEV1 by 46 mL compared to vilanterol (95% CI: 8, 83 mL, p = 0.017). At day 168 fluticasone furoate/ vilanterol 100 microgram/25 microgram and vilanterol increased adjusted mean weighted mean FEV1 over 0-4 hours by 193 mL (95% CI: 156, 230 mL, p < 0.001) and 145 mL (95% CI: 108, 181 mL, p < 0.001) respectively compared to placebo. Fluticasone furoate/ vilanterol 100/25 microgram increased adjusted mean weighted mean FEV1 over 0-4 hours by 148 mL compared to FF alone (95% CI: 112, 184 mL, p < 0.001).
In both the HZC112206 and HZC112207 studies, at day 168, differences were seen in the adjusted mean change from baseline CRQ-SAS dyspnoea scores between the fluticasone furoate/ vilanterol 100 microgram/25 microgram and placebo groups (HZC112206: 0.30, (95% CI 0.06, 0.54, p = 0.014); HZC112207: 0.24, (95% CI 0.02, 0.46, p = 0.029) and between the fluticasone furoate/ vilanterol 100 microgram/25 microgram and FF 100 microgram groups (HZC112206: 0.24, (95% CI 0.01,0.48, p = 0.044); HZC112207: 0.36, (95% CI (0.14, 0.57), p = 0.001). For all the other pairwise treatment comparisons at day 168 for the CRQ-SAS dyspnoea score, the p-value was > 0.05. In both studies, none of the treatment comparisons at day 168 achieved a minimal clinically important difference (> 0.5 point improvement) in mean CRQ-SAS dyspnoea domain scores. Patients treated with fluticasone furoate/ vilanterol 100 microgram/25 microgram also had significantly less cough and sputum, required significantly less rescue medication as measured by number of occasions of rescue salbutamol use (per 24 hour period) and number of night time awakenings requiring salbutamol (per 24 hour period) compared to placebo.

12 month studies.

Studies HZC102970 and HZC102871 were 52 week randomised, double blind, parallel group, studies comparing the effect of fluticasone furoate/ vilanterol 200 microgram/25 microgram, fluticasone furoate/ vilanterol 100 microgram/25 microgram, fluticasone furoate/ vilanterol 50 microgram/25 microgram with vilanterol 25 microgram, all administered once daily, on the annual rate of moderate/ severe exacerbations in subjects with COPD with a smoking history of at least 10 pack years and a post-salbutamol FEV1/FVC ratio less than or equal to 0.70 and post-salbutamol FEV1 less than or equal to 70% predicted and documented history of ≥ 1 COPD exacerbation that required antibiotics and/or oral corticosteroids or hospitalisation in the 12 months prior to visit 1. The primary endpoint was the annual rate of moderate and severe exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or inpatient hospitalisation. Both studies had a 4 week run-in period during which all subjects received open label FP/salmeterol 250/50 twice daily to standardise COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Prior to run-in, subjects discontinued use of previous COPD medications except short acting bronchodilators. The use of concurrent inhaled long acting bronchodilators (beta2-agonist and anticholinergic), ipratropium/ salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as needed basis throughout the studies.
The results of an integrated analysis showed that treatment with fluticasone furoate/ vilanterol 100/25 microgram once daily resulted in a 27% reduction in the annual rate of moderate or severe COPD exacerbations compared with vilanterol (95% CI: 0.63, 0.84 (p < 0.001). Similar reductions in the time to first exacerbation and exacerbations requiring systemic corticosteroid use were observed with fluticasone furoate/ vilanterol 100/25 microgram once daily. See Table 7.
In an integrated analysis of HZC102970 and HZC102871 at week 52, an improvement was seen when comparing the fluticasone furoate/ vilanterol 100 microgram/25 microgram vs. vilanterol 25 microgram in adjusted mean trough FEV1 (42 mL 95% CI: 19, 64 mL, p < 0.001). The 24 hour bronchodilator effect of fluticasone furoate/ vilanterol was maintained from the first dose throughout a one year treatment period with no evidence of loss in efficacy (no tachyphylaxis).
Overall, across the two studies combined 2,009 (62%) patients had cardiovascular history/ risk factors at screening. The incidence of cardiovascular history/ risk factors was similar across the treatment groups with patients in the cardiovascular history/ risk factors subgroup most commonly suffering from hypertension (46%), followed by hypercholesterolemia (29%) and diabetes mellitus (12%). Similar effects in reduction of moderate and severe exacerbations were observed in this subgroup as compared with the overall population. In patients with a cardiovascular history/ risk factors, fluticasone furoate/ vilanterol 100 microgram/25 microgram resulted in a significantly lower annual rate of moderate/ severe COPD exacerbations compared with vilanterol (adjusted mean annual rates of 0.83 and 1.18 respectively, 30% reduction (95% CI 16, 42%, p < 0.001). Improvements were also seen in this subgroup at week 52 when comparing the fluticasone furoate/ vilanterol 100 microgram/25 microgram vs. vilanterol 25 microgram in adjusted mean trough FEV1 (44 mL 95% CI: 15, 73 mL, (p = 0.003).

Long-term study.

SUMMIT was a multi-centre, randomised, double-blind study evaluating the effect on survival of fluticasone furoate/vilanterol 100/25 micrograms compared with placebo. 16,590 patients were randomised and of these, 16,485 subjects were included in the intent-to-treat efficacy population. Subjects were treated for up to 4 years (mean 1.7 years) with either fluticasone furoate/vilanterol 100/25 micrograms, fluticasone furoate 100 micrograms, vilanterol 25 micrograms, or placebo. All subjects had COPD with moderate airflow limitation (≥ 50% and ≤ 70% predicted FEV1) and a history of, or an increased risk of, cardiovascular (CV) disease. The primary endpoint was all-cause mortality, while secondary endpoints were a composite of cardiovascular events (on-treatment cardiovascular death, myocardial infarction, stroke, unstable angina, or transient ischemic attack) and the rate of decline in post-bronchodilator FEV1. In the year prior to study start, 39% of subjects experienced at least one COPD exacerbation and 15% experienced 2 or more COPD exacerbations. Prior to the start of the study, 35% of subjects were taking long-acting beta2 agonists and 15% were taking long-acting anti-cholinergic medications - these medications were stopped prior to study entry per protocol. The patient baseline characteristics described above are provided in Table 8 per treatment arm.
All-cause mortality was not statistically significantly different between placebo and fluticasone furoate/vilanterol (HR 0.878; 95% CI: 0.739, 1.042). All-cause mortality (per 100 patient-years) was 3.1 for fluticasone furoate/vilanterol, 3.5 for placebo, 3.2 for fluticasone furoate, and 3.4 for vilanterol.
The mean rate of decline in FEV1 was fluticasone furoate/vilanterol, 38 mL/year; placebo, 46 mL/year; fluticasone furoate, 38 mL/year; and vilanterol, 47 mL/year.
The incidence of cardiovascular composite events (per 100 patient-years of treatment exposure) was 2.5 for fluticasone furoate/vilanterol, 2.7 for placebo, 2.4 for fluticasone furoate, and 2.6 for vilanterol.
The annual rate of severe exacerbations per patient per year (requiring hospitalisation) was 0.05 for fluticasone furoate/vilanterol, 0.07 for placebo, 0.06 for fluticasone furoate, and 0.06 for vilanterol. See Table 9.

Studies versus salmeterol/ fluticasone propionate combinations.

In a 12 week study (HZC113107) in COPD patients both fluticasone furoate/ vilanterol 100 microgram/25 microgram given once daily in the morning and FP/salmeterol 500/50 microgram given twice daily, demonstrated improvements from baseline in lung function. Adjusted mean treatment increases from baseline in weighted mean 0-24 hours FEV1 of 130 mL (fluticasone furoate/ vilanterol) and 108 mL (FP/salmeterol) demonstrated an overall improvement in lung function over 24 hours for both treatments. The adjusted mean treatment difference of 22 mL (95% CI: -18, 63 mL) between the groups was not statistically significant (p = 0.282). A clinically meaningful mean improvement was achieved for mean change from baseline in SGRQ Total Score after 12 weeks of treatment for the fluticasone furoate/ vilanterol 100 microgram/25 microgram once daily treatment group (-4.78) but not for the FP/salmeterol 500/50 twice daily treatment group (-3.29). The adjusted mean treatment difference was -1.50 (p = 0.215. 95% CI (-3.86, 0.87)).

5.2 Pharmacokinetic Properties

Absorption.

The absolute bioavailability for fluticasone furoate and vilanterol when administered by inhalation as fluticasone furoate/ vilanterol was on average 15.2% and 27.3%, respectively. The oral bioavailability of both fluticasone furoate and vilanterol was low, on average 1.26% and < 2%, respectively. Given this low oral bioavailability, systemic exposure for fluticasone furoate and vilanterol following inhaled administration is primarily due to absorption of the inhaled portion of the dose delivered to the lung.

Distribution.

Following intravenous dosing, both fluticasone furoate and vilanterol are extensively distributed with average volumes of distribution at steady state of 661 L and 165 L, respectively.
Both fluticasone furoate and vilanterol have a low association with red blood cells. In vitro plasma protein binding in human plasma of fluticasone furoate and vilanterol was high, on average > 99.6% and 93.9%, respectively. There was no decrease in the extent of in vitro plasma protein binding in subjects with renal or hepatic impairment.
Fluticasone furoate and vilanterol are substrates for P-glycoprotein (P-gp), however, concomitant administration of fluticasone furoate/ vilanterol with P-gp inhibitors is considered unlikely to alter fluticasone furoate or vilanterol systemic exposure since they are both well absorbed molecules.

Metabolism.

Based on in vitro data, the major routes of metabolism of both fluticasone furoate and vilanterol in human 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.
Vilanterol is primarily metabolised by O-dealkylation to a range of metabolites with significantly reduced β1- and β2-agonist activity.
A repeat dose CYP3A4 drug interaction study was performed in healthy subjects with the fluticasone furoate/ vilanterol combination (200/25) and the strong CYP3A4 inhibitor ketoconazole (400 mg). Coadministration 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 h weighted mean serum cortisol. Coadministration increased mean vilanterol AUC(0-t) and Cmax 65% and 22%, respectively. The increase in vilanterol exposure was not associated with an increase in beta-agonist related systemic effects on heart rate, blood potassium or QTcF interval.

Excretion.

Following oral administration, fluticasone furoate was eliminated in humans mainly by metabolism with metabolites being excreted almost exclusively in faeces, with < 1% of the recovered radioactive dose eliminated in the urine. The apparent plasma elimination half-life of fluticasone furoate following inhaled administration of fluticasone furoate/ vilanterol was, on average, 24 hours.
Following oral administration, vilanterol was eliminated in humans mainly by metabolism followed by excretion of metabolites in urine and faeces of approximately 70% and 30% of the radioactive dose, respectively. The apparent plasma elimination half-life of vilanterol following inhaled administration of fluticasone furoate/ vilanterol was, on average, 2.5 hours.

Special patient populations.

Population PK meta-analyses for fluticasone furoate and vilanterol were conducted in phase III studies in subjects with asthma or COPD. The impact of demographic covariates (age, gender, weight, BMI, racial group, ethnicity) on the pharmacokinetics of fluticasone furoate and vilanterol were evaluated as part of the population pharmacokinetic analysis.

Race.

In elderly subjects with asthma or COPD estimates of fluticasone furoate AUC(0-24) for East Asian, Japanese and South Asian subjects (12-14% subjects) were up to 53% higher on average compared with Caucasian subjects. However, there was no evidence for the higher systemic exposure in these populations to be associated with greater effect on 24 hour urinary cortisol excretion. There was no effect of race on pharmacokinetic parameter estimates of vilanterol in subjects with COPD.
In subjects with asthma, on average, vilanterol Cmax is estimated to be 220 to 287% higher and AUC(0-24) comparable for those subjects from an Asian heritage compared with subjects from other racial groups. However, there was no evidence that this higher vilanterol Cmax resulted in clinically significant effects on heart rate.

Children.

Breo Ellipta should not be used in children (i.e. patients younger than 12 years of age).
In adolescents (12 years or older), there are no recommended dose modifications.

Elderly.

The effects of age on the pharmacokinetics of fluticasone furoate and vilanterol were determined in phase III studies in COPD and asthma.
There was no evidence for age (12-84) to affect the PK of fluticasone furoate or vilanterol in subjects with asthma.
There was no evidence for age to affect the PK of fluticasone furoate in subjects with COPD while there was an increase (37%) in AUC(0-24) of vilanterol over the observed age range of 41 to 84 years. For an elderly subject (aged 84 years) with low bodyweight (35 kg) vilanterol AUC(0-24) is predicted to be 35% higher than the population estimate (subject with COPD aged 60 years and bodyweight of 70 kg), whilst Cmax was unchanged. These differences are unlikely to be of clinical relevance.

Renal impairment.

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. No dose adjustment is required for patients with renal impairment.
The effects of haemodialysis have not been studied.

Hepatic impairment.

Following repeat dosing of fluticasone furoate/ vilanterol for 7 days, there was an increase in fluticasone furoate systemic exposure (up to threefold as measured by AUC(0-24)) in subjects with hepatic impairment (Child-Pugh A, B or C) compared with healthy subjects. The increase in fluticasone furoate systemic exposure (fluticasone furoate/ vilanterol 200/25 microgram) in subjects with moderate hepatic impairment (Child-Pugh B) 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 a lower dose of 100/12.5 microgram there was no reduction in serum cortisol. For patients with moderate or severe hepatic impairment the maximum dose is 100/25 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.

Gender, weight and BMI.

There was no evidence for gender, weight or BMI to influence the pharmacokinetics of fluticasone furoate based on a population pharmacokinetic analysis of phase III data in 1,213 subjects with asthma (712 females) and 1,225 subjects with COPD (392 females).
There was no evidence for gender, weight or BMI to influence the pharmacokinetics of vilanterol based on a population pharmacokinetic analysis in 856 subjects with asthma (500 females) and 1,091 subjects with COPD (340 females).
No dosage adjustment is necessary based on gender, weight or body mass index (BMI).

5.3 Preclinical Safety Data

Genotoxicity.

Fluticasone furoate was not genotoxic in a standard battery of studies.
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/ vilanterol triphenylacetate combination.
Fluticasone furoate was not carcinogenic in lifetime inhalation studies in rats or mice at exposures similar to those at the maximum recommended human dose, based on AUC.
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 1 or 30-fold, respectively, those at the maximum recommended human dose, based on AUC.

4 Clinical Particulars

4.1 Therapeutic Indications

COPD.

Breo Ellipta is indicated for symptomatic treatment of patients with COPD with a FEV1 70% predicted normal (post-bronchodilator) in patients with an exacerbation history despite regular bronchodilator therapy.
Breo Ellipta is not indicated for the initiation of bronchodilator therapy in COPD.

Asthma.

Breo Ellipta is indicated in the regular treatment of moderate to severe asthma in patients who require a medium to high dose inhaled corticosteroid combined with a long acting beta2-agonist.
Vilanterol, an active ingredient in Breo Ellipta, is a long acting beta2-agonist (LABA). A class effect of all LABAs can be an increased risk of asthma death (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Precautions for use.

Vilanterol, an active ingredient in Breo Ellipta, is a long acting beta2-agonist (LABA). Limited postmarketing data are available for vilanterol; however, postmarketing data for other LABAs show that LABAs can be associated with an increased risk of asthma death. This is considered a class effect of all LABAs.
Fluticasone furoate 100 microgram is a medium dose of inhaled corticosteroid and fluticasone furoate 200 microgram is a high dose of inhaled corticosteroid. Medium to high doses of inhaled corticosteroids may cause systemic effects. These include growth retardation in adolescents (see Section 4.4 Special Warnings and Precautions for Use, Systemic corticosteroid effects).
Breo Ellipta should only be used for patients not adequately controlled on a long-term, asthma control medication, such as an inhaled corticosteroid. Patients should be assessed at regular intervals. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. In patients whose asthma is well controlled and stable with the lowest strength of Breo Ellipta, the next step should consider cessation of Breo Ellipta and transfer to maintenance therapy with an inhaled corticosteroid alone.
Breo Ellipta should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using Breo Ellipta should not use another medicine containing a LABA (e.g. salmeterol, eformoterol, indacaterol) for any reason.
Breo Ellipta 200/25 microgram is not recommended for patients with COPD (see Section 4.2 Dose and Method of Administration).

Deterioration of disease.

Breo Ellipta should not be used to treat acute asthma symptoms or an acute exacerbation in COPD, for which a 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 with asthma or COPD should have a personal action plan designed in association with their general practitioner. Patients should not stop therapy with Breo Ellipta, in asthma or COPD, without physician supervision since symptoms may recur after discontinuation.
Serious and potentially life threatening, asthma related adverse events and exacerbations may occur during treatment with Breo Ellipta. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of fluticasone furoate/ vilanterol.

Paradoxical bronchospasm.

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a short acting inhaled bronchodilator. Breo Ellipta should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Cardiovascular effects (see Section 4.8 Adverse Effects (Undesirable Effects)).

Cardiovascular effects, such as cardiac arrhythmias, e.g. supraventricular tachycardia and extrasystoles may be seen with sympathomimetic drugs, including fluticasone furoate/ vilanterol. In addition, beta2-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Therefore Breo Ellipta should be used with caution in patients with severe cardiovascular disease.

Use in hepatic impairment.

For patients with moderate to severe hepatic impairment, the 100/25 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 and 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, growth retardation in children and adolescents, and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).
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.

Hyperglycaemia.

There have been reports of increases in blood glucose levels with fluticasone furoate/vilanterol. This should be considered in patients with a history of, or with risk factors for, diabetes mellitus (see Section 4.8 Adverse Effects (Undesirable Effects)).

Pneumonia.

An increase in pneumonia has been observed in patients with COPD receiving fluticasone furoate/ vilanterol. There was also an increased incidence of pneumonias resulting in hospitalisation. In some incidences these pneumonia events were fatal (see Section 5.1 Pharmacodynamic Properties, Clinical trials and Section 4.8 Adverse Effects (Undesirable Effects)). 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. Risk factors for pneumonia in patients with COPD receiving fluticasone furoate/ vilanterol include current smokers, patients with a history of prior pneumonia, patients with a body mass index < 25 kg/m2 and patients with a (forced expiratory volume) FEV1 < 50% predicted. These factors should be considered when Breo Ellipta is prescribed and treatment should be re-evaluated if pneumonia occurs.
Breo Ellipta 200/25 microgram is not indicated for patients with COPD. There is a potential increased risk of pneumonia and systemic corticosteroid related adverse reactions with fluticasone furoate/ vilanterol 200/25 microgram (see Section 4.8 Adverse Effects (Undesirable Effects)).
The incidence of pneumonia in patients with asthma taking fluticasone furoate/ vilanterol 200/25 microgram was numerically higher compared with those receiving fluticasone furoate/ vilanterol 100/25 or placebo (see Section 4.8 Adverse Effects (Undesirable Effects)). No risk factors were identified.

Sensitivity to sympathomimetic amines.

Breo Ellipta, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or hyperthyroidism and in those who are unusually responsive to sympathomimetic amines.

Hypokalaemia and hyperglycaemia.

Beta-adrenergic agonist medicines may produce significant hypokalaemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medications may produce transient hyperglycaemia in some patients. In clinical trials evaluating fluticasone furoate/ vilanterol in subjects with asthma or COPD, there was no evidence of a treatment effect on serum glucose or potassium.

Use in the elderly.

Due to limited data in patients with asthma aged 75 years and older, Breo Ellipta 200/25 is not recommended.

Paediatric use.

Breo Ellipta should not be used in children (i.e. patients younger than 12 years of age).

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 or vilanterol 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. Concurrent use of both nonselective 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 liver enzyme CYP3A4.
Care is advised when coadministering 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 and vilanterol are both substrates of P-gp. A clinical pharmacology study in healthy subjects with coadministered vilanterol and the potent P-gp and moderate CYP3A4 inhibitor verapamil did not show any significant effect on the pharmacokinetics of vilanterol. Clinical pharmacology studies with a specific P-gp inhibitor and fluticasone furoate have not been conducted.

Interaction with sympathomimetic medicinal products.

Concomitant administration of other sympathomimetic agents (alone or as part of combination therapy) may potentiate the undesirable effects of Breo Ellipta. Breo Ellipta should not be used in conjunction with other long acting beta2-adrenergic agonists or medicinal products containing long acting beta2-adrenergic agonists.

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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no fertility data in humans. Studies in rats showed no effect of vilanterol or fluticasone furoate on male or female fertility.
(Category B3)
There are no adequate and well controlled trials with fluticasone furoate/ vilanterol in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systematically at relatively low dosage levels.
Maternal and fetal toxicity (likely due to the fluticasone furoate component) were observed in rat embryofetal development study with the fluticasone/ vilanterol combination at fluticasone furoate doses of 29.5 and 82 microgram/kg/day, respectively (equivalent to 3 and 9 times, respectively, the clinical exposure based on AUC).
In rabbits, there was evidence of maternal toxicity and embryotoxicity following inhalation exposure to vilanterol triphenylacetate at 591 and 62.7 microgram/kg/day, respectively (equivalent to 150 and 14 times the clinical exposure based on AUC). A nondose 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 1000 times the clinical exposure based on AUC) with a NOAEL of 30 microgram/kg/day (equivalent to 84 times the clinical exposure based on AUC).
Administration of Breo Ellipta to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.
There is limited information on the excretion of fluticasone furoate or vilanterol or their metabolites in human milk. However, other corticosteroids and beta2-agonists are detected in human milk. A risk to breastfed newborns/ infants cannot be excluded.
A decision must be made whether to discontinue breastfeeding or to discontinue Breo Ellipta therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The most frequent adverse events, based on studies including a comparator, are presented in Table 2 and Table 3 for asthma and COPD, respectively.
Data from large asthma and COPD clinical trials were used to determine the frequency of adverse reactions associated with fluticasone furoate/ vilanterol. In the asthma clinical development program a total of 7,034 patients were included in an integrated assessment of adverse reactions. In the COPD clinical development program a total of 6,237 subjects were included in an integrated assessment of adverse reactions.
With the exception of pneumonia and fractures, the safety profile was similar in patients with asthma and COPD. During clinical studies, pneumonia and fractures were more frequently observed in patients with COPD.
These adverse reactions are listed by system organ class and frequency. 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. See Table 4.

Description of selected adverse reactions.

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

In two replicate 12-month studies in a total of 3,255 patients with COPD (mean post-bronchodilator screening FEV1 45% of predicted, standard deviation (SD) 13%) who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia (6%-7%) reported in patients receiving the fluticasone furoate (at strengths of 50, 100, and 200 microgram)/ vilanterol 25 microgram combination than in those receiving vilanterol 25 microgram alone (3%). Pneumonia which required hospitalisation occurred in 3% of patients receiving fluticasone furoate/ vilanterol (all strengths) and in < 1% of patients receiving vilanterol. In these studies, nine fatal cases of pneumonia were reported. Of these, seven were reported during treatment with fluticasone furoate/ vilanterol 200/25 microgram, one during treatment with fluticasone furoate/ vilanterol 100/25 microgram and one post-treatment with vilanterol monotherapy. Risk factors for pneumonia observed in these studies included current smokers, patients with a history of prior pneumonia, patients with a body mass index < 25 kg/m2 and patients with an FEV1 < 50% predicted (see Section 4.4 Special Warnings and Precautions for Use).
In SUMMIT, a multi-centre, randomised study (HZC113782), 16,568 subjects (safety population) received fluticasone furoate/vilanterol 100/25 micrograms, fluticasone furoate 100 micrograms, vilanterol 25 micrograms or placebo for a mean of 1.7 years. Subjects had moderate COPD (mean post-bronchodilator screening FEV1 60% of predicted, SD 6%) and a history of, or an increased risk of, cardiovascular disease. The annualised event rate (per 1000 treatment-years) of serious pneumonia was 22.4 for fluticasone furoate/vilanterol 100/25, 25.1 for fluticasone furoate 100 micrograms, 16.4 for vilanterol 25 micrograms, and 22.2 for placebo. The annualised event rate (per 1000 treatment-years) for adjudicated, on-treatment deaths due to pneumonia was 1.8 for fluticasone furoate/vilanterol 100/25, 1.5 for fluticasone furoate 100 micrograms, 0.9 for vilanterol 25 micrograms, and 1.4 for placebo.
In an integrated analysis of 11 studies in asthma (7,034 patients), the incidence of pneumonia (adjusted for exposure, due to low numbers and limited number of patients on placebo) seen with fluticasone furoate/ vilanterol 100/25 microgram strength (9.6/1000 patient years) was similar to placebo (8.0/1000 patient years). There was a higher incidence of pneumonia in the 200/25 microgram strength (18.4/1000 patient years) compared to the 100/25 microgram strength. Few of the pneumonia events led to hospitalisation with either strength, and there were no observed differences in the incidence of serious events between the two treatment strengths.

Cardiovascular events (see Section 4.4 Special Warnings and Precautions for Use).

For the SUMMIT study (see description above), the annualised event rate (per 1000 treatment-years) of serious cardiovascular events was 64.5 for fluticasone furoate/vilanterol 100/25, 58.1 for fluticasone furoate 100 micrograms, 59.2 for vilanterol 25 micrograms, and 63.2 for placebo. The annualised event rate (per 1000 treatment-years) for adjudicated cardiovascular deaths was 11.7 for fluticasone furoate/vilanterol 100/25, 11.6 for fluticasone furoate 100 micrograms, 12.9 for vilanterol 25 micrograms, and 13.0 for placebo.

** Fractures.

In two replicate 12 month studies in a total of 3,255 patients with COPD the incidence of bone fractures overall was low in all treatment groups, with a higher incidence in all fluticasone furoate/ vilanterol groups (2%) compared with the vilanterol 25 microgram group (< 1%). Although there were more fractures in the fluticasone furoate/ vilanterol groups compared with the vilanterol 25 microgram group, fractures typically associated with corticosteroid use (e.g. spinal compression/ thoracolumbar vertebral fractures, hip and acetabular fractures) occurred in < 1% of the fluticasone furoate/ vilanterol and vilanterol treatment arms.
In an integrated analysis of 11 studies in asthma (7,034 patients), the incidence of fractures was < 1%, and usually associated with trauma.

Postmarketing data.

There are limited postmarketing data available. Because of the limited long-term safety data (beyond one year) for Breo Ellipta, assumptions about long-term safety for this combination product have been based on data from pharmaceuticals in the same class. 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.

4.2 Dose and Method of Administration

Dose.

Asthma.

Patients should be made aware that Breo 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 Breo Ellipta they are receiving remains optimal and is only changed on medical advice. To minimise adverse reactions, inhaled corticosteroids should be used at the lowest dose that maintains symptom control.

Adults and adolescents aged 12 years and over.

The recommended dose of Breo Ellipta is:
one inhalation of Breo Ellipta 100/25 microgram once daily or one inhalation of Breo Ellipta 200/25 microgram once daily.
A starting dose of Breo Ellipta 100/25 microgram should be considered for patients who require a mid dose of inhaled corticosteroid in combination with a long acting beta2-agonist.
Breo Ellipta 200/25 microgram should be considered for patients who require a higher dose of inhaled corticosteroid in combination with a long acting beta2-agonist.
If patients are inadequately controlled on Breo Ellipta 100/25 microgram, consider increasing the dose to 200/25 microgram, which may provide additional improvement in asthma control.
See Table 1.
Prescribers should be aware that 100 microgram of fluticasone furoate is a medium dose of inhaled corticosteroid and 200 microgram of fluticasone furoate is a high dose of inhaled corticosteroid. In patients with asthma, 100 microgram of fluticasone furoate taken once daily produces similar effects to fluticasone propionate 250 microgram taken twice daily and 200 microgram of fluticasone furoate taken once daily produces similar effects to fluticasone propionate 500 microgram taken twice daily.
To minimise adverse reactions, inhaled corticosteroids should be used at the lowest dose that maintains symptom control. Patients should be assessed at regular intervals. In patients whose asthma is well controlled and stable the Breo Ellipta dose may carefully be down titrated to the lowest strength of Breo Ellipta.
The next step should consider the cessation of Breo Ellipta and transfer to an appropriate inhaled corticosteroid containing regimen. When deemed clinically appropriate the inhaled corticosteroid dose should be further adjusted to the lowest dose at which effective control of asthma is maintained.

Additional recommendations for adolescents aged 12 years and older.

Down titration to the lowest inhaled corticosteroid dose is especially important in adolescents who may be more susceptible to systemic corticosteroid effects (see Section 4.4 Special Warnings and Precautions for Use). When down titrating to another product, consideration should be given to maintaining a once daily regimen to facilitate compliance.

Children aged less than 12 years.

Breo Ellipta should not be used in children younger than 12 years of age.

COPD.

Adults.

The recommended dose of Breo Ellipta is:
one inhalation of Breo Ellipta 100/25 microgram once daily.
Breo Ellipta 200/25 microgram is not indicated for patients with COPD. There is a potential increased risk of pneumonia and corticosteroid related adverse reactions with the 200/25 microgram dose (see Section 4.4 Special Warnings and Precautions for Use and Section 4.8 Adverse Effects (Undesirable Effects)).

Asthma and COPD.

Elderly.

Due to limited data in patients with asthma aged 75 years and older, Breo Ellipta 200/25 is not recommended.

Renal impairment.

No dose adjustment is required for patients with renal impairment (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Hepatic impairment.

A clinical pharmacology study in subjects with mild, moderate and severe hepatic impairment showed up to 3-fold increase in systemic exposure to fluticasone furoate (AUC) (see Section 5.2 Pharmacokinetic Properties, Special patient populations).
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 100/25 microgram (see Section 5.2 Pharmacokinetic Properties).

Method of administration.

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

How to use Breo Ellipta.

What is the Ellipta inhaler?

Breo 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 one month from the date you first 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 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 the medicine.
Take it back to your pharmacist for advice.
Do not shake the inhaler at any time.

Step 2: inhale your medication.

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 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 if possible.
This will make it less likely that you will develop a sore mouth or throat as side effects.

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of fluticasone furoate/ vilanterol on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the pharmacology of fluticasone furoate or vilanterol.

4.9 Overdose

Symptoms and signs.

There are no data available from clinical trials on overdose with Breo Ellipta.
An overdose of Breo Ellipta may produce signs and symptoms due to the individual components' actions, including those seen with overdose of other beta2-agonists and consistent with the known inhaled corticosteroid class effects (see Section 4.4 Special Warnings and Precautions for Use).

Treatment.

There is no specific treatment for an overdose with Breo 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 Poison Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

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 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 an hour before use.

6.5 Nature and Contents of Container

Breo Ellipta is a moulded plastic inhaler with a light grey body, a pale blue mouthpiece cover and a dose counter, packed in a foil tray which contains a desiccant sachet. The tray is sealed with a peelable lid.
The inhaler contains two strips of either 30 or 14 regularly distributed blisters.
Not all pack sizes 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.

Summary Table of Changes