Consumer medicine information

Flutiform Inhaler

Fluticasone propionate; Formoterol (eformoterol) fumarate dihydrate

BRAND INFORMATION

Brand name

Flutiform

Active ingredient

Fluticasone propionate; Formoterol (eformoterol) fumarate dihydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Flutiform Inhaler.

What is in this leaflet

This leaflet answers some common questions about FLUTIFORM pressurised inhalation ("inhaler").

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

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

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

What FLUTIFORM inhaler is used for

FLUTIFORM inhaler is used to help with asthma in people who need regular treatment.

Asthma is a disease where the lining of the lungs become inflamed (red and swollen), making it difficult to breathe. This may be due to an allergy to house dust mites, smoke, air-borne pollution or other irritants. Symptoms of asthma include shortness of breath, wheezing, chest tightness and cough.

FLUTIFORM inhaler contains two different medicines called fluticasone propionate and formoterol (eformoterol) fumarate dihydrate.

Fluticasone propionate belongs to a group of medicines known as corticosteroids, frequently called 'steroids'. They are not 'anabolic steroids' which are sometimes misused by athletes. Corticosteroids help to reduce swelling and inflammation in the lungs.

Formoterol (Eformoterol) fumarate dihydrate belongs to a group of medicines known as long-acting beta-2-agonists. Beta-2-agonists help the airways in your lungs to stay open, making it easier for you to breathe.

When used together regularly, fluticasone propionate and formoterol (eformoterol) fumarate dihydrate help to control your asthma symptoms and prevent asthma attacks. FLUTIFORM inhaler is known as a 'preventer'. It does not work if you are already having an asthma attack, i.e. you are already wheezing and breathless. You will need to use a fast acting 'reliever' medicine if this happens.

Your doctor may have prescribed it for another reason.

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

FLUTIFORM inhaler is not addictive.

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

Before you use FLUTIFORM inhaler

When you must not use it

Do not use FLUTIFORM inhaler if you are allergic to fluticasone propionate, formoterol (eformoterol) fumarate dihydrate or any of the other ingredients listed at the end of this leaflet. Symptoms of an allergic reaction may include wheezing, swelling of the lips/mouth or other parts of the body, difficulty in breathing, lumpy rash ("hives") or fainting.

Do not give FLUTIFORM inhaler to a child under 12 years, unless directed to by the child's doctor. FLUTIFORM inhaler is not recommended for use in children under 12 years. The safety and efficacy of FLUTIFORM inhaler have not been assessed in children under 12 years of age.

Do not use FLUTIFORM inhaler after the expiry date (EXP) printed on the pack. If you use it after the expiry date has passed, it may not work very well.

Do not use it if the packaging is torn or shows signs of tampering.

If you are not sure whether you should be using FLUTIFORM inhaler, talk to your doctor or pharmacist.

Before you start to use it

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

Tell your doctor or pharmacist if you have or have had any of the following medical conditions:

  • heart problems or disease, an irregular heartbeat or if you have been told that your heart trace is abnormal
  • an abnormal bulging of a blood vessel wall (aneurysm)
  • liver problems
  • diabetes
  • high blood pressure
  • glaucoma
  • an overactive thyroid gland
  • adrenal glands not working properly
  • tumour of the adrenal gland
  • low blood levels of potassium.

Tell your doctor or pharmacist if you currently have an infection. If you use FLUTIFORM inhaler while you have an infection, the medicine may hide some of the signs of an infection. This may make you think, mistakenly, that you are better or that it is not serious.

Tell your doctor or pharmacist if you have or have had tuberculosis (TB).

Tell your doctor or pharmacist if you are pregnant or intend to become pregnant. Your doctor or pharmacist will discuss the possible risks and benefits of using FLUTIFORM inhaler during pregnancy.

Tell your doctor or pharmacist if you are breastfeeding or plan to breastfeed. Your doctor or pharmacist will discuss the possible risks and benefits of using FLUTIFORM inhaler during breastfeeding.

Tell your doctor if you are going to have an operation, or are feeling stressed. You may need additional steroid medicine during these times.

If you have not told your doctor or pharmacist about any of the above, tell them before you use FLUTIFORM inhaler.

Taking other medicines

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

Some medicines and FLUTIFORM inhaler may interfere with each other. These include:

  • medicines to treat depression or mood/mental disorders (such as monoamine oxidase inhibitors, tricyclic antidepressants, phenothiazines), or you have taken any of these types of medicines in the last two weeks
  • medicines known as beta-blockers, which may be used to treat high blood pressure or glaucoma including those that are eye drops
  • medicines used to treat high blood pressure or fluid build-up
  • medicines used to treat heart failure (such as digoxin)
  • medicines used to treat abnormal heart rhythms (such as quinidine, disopyramide, procainamide)
  • medicines used to treat fungal infections (such as ketoconazole, itraconazole)
  • medicines used to treat viral infections, including HIV (such as ritonavir, atazanavir, indinavir, nelfinavir, saquinavir, cobicistat)
  • medicines used to treat bacterial infections (antibiotics, such as clarithromycin, telithromycin, furazolidone)
  • medicines used to treat allergies, hayfever, coughs, colds and runny nose
  • other medicines containing steroids
  • certain other medicines used to treat asthma or breathing conditions (such as theophylline or aminophylline)
  • medicines used for weight reduction purposes
  • medicine to treat Hodgkin's disease (procarbazine)
  • medicine to treat Parkinson's disease (levodopa)
  • medicine used to treat an underactive thyroid gland (levothyroxine)
  • medicine to induce labour (oxytocin)
  • alcohol.

If you are going to have an operation under a general anaesthetic, please tell the doctor at the hospital that you are using this inhaler.

These medicines may be affected by or may affect FLUTIFORM inhaler. If you are taking these medicines, talk to your doctor or pharmacist who will advise you on what to do. You may need to use different amounts of your medicines, or take different medicines.

FLUTIFORM inhaler contains a very small amount of sodium cromoglycate, however patients who are currently using cromoglycate (to treat conditions such as asthma, allergic rhinitis and allergic conjunctivitis) should continue their normal medication.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while using FLUTIFORM inhaler.

How to use FLUTIFORM inhaler

How much to use

Follow the instructions given to you by your doctor and pharmacist.

Your doctor or pharmacist will tell you exactly how much to use.

Adults and adolescents 12 years and older:
Your doctor will decide what dose and what strength of FLUTIFORM inhaler you should use, depending on the severity of your asthma.

The usual dose is two inhalations twice a day; two in the morning and two in the evening.

Adolescents should not use the highest strength inhaler (FLUTIFORM inhaler 250 micrograms/10 micrograms).

How to use it

The instructions for using FLUTIFORM inhaler are given in this leaflet. You should check with your doctor or pharmacist if you are not sure how to use FLUTIFORM inhaler.

The medicine is contained in an aerosol can (canister) (see Diagram 1) which sits inside a plastic dispenser (also known as an actuator). The actuator has a colour-coded dose counter which displays the remaining actuations in increments of 10, down to 60 doses, and in increments of 5 thereafter. The numbers are separated by a dot. The indicator is initially green (120 to 45 puffs remaining), then yellow (45 to 25 puffs remaining), and then red (25 to 0 puffs remaining). When the indicator turns red, you should be contacting your doctor or returning to your pharmacy to have a replacement dispensed. Do not remove the canister from the actuator as this can interfere with the dose counter.

Before you use your inhaler for the first time, or if it has not been used for more than 3 days, it needs to be 'primed' to ensure it works properly and gives you the correct dose.

To 'prime' the inhaler:

  • Remove the mouthpiece cover and shake the inhaler well.
  • Spray away from your face by pressing down on the canister. This step should be performed 4 times.

Also, in case of freezing conditions, the inhaler must be primed. Allow 30 minutes warm up to room temperature, and then spray away from your face 2 times before use.

Using your inhaler:

The medicine in FLUTIFORM inhaler must only be breathed into your lungs through the mouth.

  1. Remove the mouthpiece cover and check that your mouthpiece is clean and free from any dust. The inhaler should be shaken immediately before releasing each puff.
  2. Sit upright or stand. Breathe out slowly and as deeply as possible.

  1. Hold your inhaler upright (as shown in Diagram 3) and put the mouthpiece in your mouth with your lips around it. Do not bite the mouthpiece.
  2. Breathe in slowly and deeply through your mouth and, at the same time, press down on the canister to release one puff. (as shown in Diagram 4)

  1. Hold your breath for as long as possible. Finally, remove the inhaler from your mouth and breathe out slowly. Do not breathe out into the inhaler.
  2. Keep the inhaler in a vertical position for about half a minute and then shake the inhaler prior to slowly repeating Steps 2 to 5.
  3. Replace the mouthpiece cover.

Do not perform steps 2 to 5 too quickly.

If you see a 'mist' from the top of the inhaler or around your mouth when you use your inhaler, then you may not have inhaled your medicine properly. Have another dose by repeating from Step 2 above.

Always rinse your mouth out, gargle with water or brush your teeth after you have used your inhaler and spit out the residue. This may help prevent you developing a hoarse voice or sore mouth, throat or tongue.

If you have weak hands, it may be easier to hold the inhaler in both hands placing both index fingers on the canister and both thumbs on the base of the inhaler.

If you have difficulty using your inhaler, your doctor may also recommend a spacer, a device to help you use your medicine properly.

Your doctor or pharmacist will advise you how to use your spacer device with your inhaler. It should also come with instructions for use and care.

Caring for your inhaler:

It is important to clean your inhaler weekly.

To clean your inhaler:

  • Remove the mouthpiece cover.
  • Do not remove the canister from the actuator as this can interfere with the dose counter.
  • Wipe the inside and outside of the mouthpiece and the outside of the actuator with a clean, dry cloth or tissue.
  • Replace the mouthpiece cover.

DO NOT PUT THE METAL CANISTER INTO WATER.

If you have any difficulties or do not understand the instructions, talk to your doctor or pharmacist.

When to use it

FLUTIFORM inhaler is used to help people with asthma who need regular treatment.

It is very important that you use your FLUTIFORM inhaler every day, twice a day (morning and night). This will help prevent asthma symptoms throughout the day and night.

Do not use FLUTIFORM inhaler to relieve a sudden attack of breathlessness or wheezing. You will need a fast-acting 'reliever' medicine if this happens. You should carry your 'reliever' medicine with you at all times.

If you feel you are getting more breathless or wheezy more often than normal, or you are using your fast-acting 'reliever' medicine more than usual, you should talk to your doctor.

How long to use it

You must use your FLUTIFORM inhaler every day (twice a day). Do not stop using it, even if you feel better, unless your doctor tells you.

If you forget to use it

If you forget to have a dose, use it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose, then use your next dose when you are meant to.

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

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

If you have trouble remembering when to use your medicine, ask your pharmacist for hints. For example, use your medicine at the same time each morning and evening such as 8 a.m. and 8 p.m.

If you use too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have used too much FLUTIFORM inhaler.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep telephone numbers for these places handy.

If you use too much of FLUTIFORM inhaler than you should, you may experience severe chest pain (angina), high or low blood pressure, a headache, muscle cramps, difficulty in sleeping, nervousness, a dry mouth, a loss of appetite, seizures, fits or convulsions. You may feel shaky, light headed, faint, tired, sick or generally unwell. You may also notice changes in the rate of your heart beat. There may be changes to potassium and sugar levels in your blood. You may also suffer from symptoms such as abdominal pain, being sick, weight loss or decreased level of consciousness (which could make you feel drowsy or confused).

If you have used more than the prescribed dose for a long period of time, you should talk to your doctor or pharmacist for advice.

When seeking medical attention, take this leaflet and your inhaler with you to show the doctor.

While you are using FLUTIFORM inhaler

Things you must do

Use FLUTIFORM inhaler exactly as your doctor has prescribed.

Before you start on a new medicine, remind your doctor and pharmacist that you are using FLUTIFORM inhaler.

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

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

Tell your doctor if you are going to have an operation, have had an accident or have a severe infection.

If your body is stressed, you may need other medicines.

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

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

Tell your doctor as soon as possible if:

  • you are getting more breathless or wheezy
  • you are using your 'reliever' medicine more than usual
  • your 'reliever' medicine does not help your breathing as much as usual
  • the effect of your 'reliever' medicine does not last as long as usual
  • you need more doses of your 'reliever' medicine than usual to get relief.

Tell your doctor if, for any reason, you have not used your medicine exactly as prescribed. Otherwise your doctor may think that your medicine was not effective and change your treatment unnecessarily.

If you have used more than the prescribed dose for a long time, you should talk to your doctor for advice. This is because large doses may reduce the amount of steroid hormones produced by your body.

Make sure you have enough doses of FLUTIFORM inhaler with you to last over weekends and holidays.

Things you must not do

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

Do not use FLUTIFORM inhaler to treat any other complaint unless your doctor tells you to.

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

Do not stop using FLUTIFORM inhaler or change the dosage without checking with your doctor. If you need to stop using FLUTIFORM inhaler, your doctor will tell you how to do this. Usually your dose will be gradually reduced each day, before stopping the medicine completely. This is to reduce the risk of triggering an asthma attack.

Do not use FLUTIFORM inhaler to treat an acute asthma attack.

Things to be careful of

Be careful driving or operating machinery until you know how FLUTIFORM inhaler affects you. FLUTIFORM inhaler is unlikely to affect your ability to drive or operate machinery. However, as with many other medicines, some people may experience blurred vision, dizziness or spinning sensation, light-headedness or tiredness.

Tell your doctor or pharmacist if you notice that you have a sore mouth, throat or tongue, sore, creamy-yellow, raised patches in the mouth or a hoarse voice. These problems are less likely to happen if you use a spacer or rinse your mouth out each time after using FLUTIFORM inhaler.

Side effects

All medicines may have some unwanted side effects. Sometimes they are serious but most of the time they are not. You may need medical treatment if you get some of the side effects. Your doctor has weighed the risks of FLUTIFORM inhaler against the benefits they expect it will have for you.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

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

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

If you get any side effects, do not stop using FLUTIFORM inhaler without first talking to your doctor or pharmacist.

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

  • headaches
  • dizziness or spinning sensation
  • shaking or tremors
  • changes in taste
  • hoarse voice
  • dry mouth
  • irritated throat
  • raised patches in the mouth
  • sore mouth, throat or tongue
  • inflammation of the sinuses, runny or blocked nose
  • diarrhoea
  • nausea, vomiting
  • indigestion
  • muscle spasms or pain
  • abnormal dreams or difficulty in sleeping
  • agitation or anxiety
  • tiredness or unusual weakness
  • swelling of legs and ankles
  • an increase in the amount of sugar in your blood
  • blurred vision or other visual disturbances.

Tell your doctor or pharmacist immediately if you notice any of the following:

  • irregular heart beat or palpitations
  • chest pain
  • bruising
  • feeling nervous or restless
  • mood changes
  • worsening of your asthma (shortness of breath, coughing).

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

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

  • you have an allergic reaction: shortness of breath, wheezing, shallow or difficult breathing; swelling of the tongue, throat, face, lips or other parts of the body; rash, itching or hives on the skin.

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

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

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

After using FLUTIFORM inhaler

Storage

Keep your inhaler in a cool, dry place, where the temperature stays below 25°C.

Do not keep your inhaler in the refrigerator or freezer.

Do not store it or any other medicine in the bathroom, near a sink or on a window sill. Do not leave it in the car on hot days. Heat and damp 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.

Do not use the inhaler if it has been removed from the foil pouch for over 3 months, or if the dose counter reads "0" (whichever comes first).

WARNING: The canister contains a pressurised liquid. Do not puncture, break or burn the can even when apparently empty.

Disposal

If your doctor tells you to stop using the inhaler, the inhaler has been removed from the foil pouch for over 3 months, the dose counter reads "0", or if the inhaler has passed their expiry date, ask your pharmacist how to dispose of medicines no longer required.

Product description

What it looks like

FLUTIFORM® inhalers are pressurised metered-dose inhalers. The inhalers are small canisters containing a white to off-white liquid suspension fitted with a metering valve. The canisters are inserted into plastic dispensers (actuators) fitted with a dust cap and a dose indicator which indicates the number of doses remaining. Each inhaler contains 120 actuations (puffs).

They are available in three strengths:

  • 50 micrograms/5 micrograms
  • 125 micrograms/5 micrograms
  • 250 micrograms/10 micrograms.

FLUTIFORM® inhalers are packed in foil pouches within a box containing one inhaler.

Ingredients

Active ingredients:

Each dose contains:

  • 50 micrograms of fluticasone propionate/5 micrograms of formoterol (eformoterol) fumarate dihydrate
  • 125 micrograms of fluticasone propionate/5 micrograms of formoterol (eformoterol) fumarate dihydrate
  • 250 micrograms of fluticasone propionate/ 10 micrograms of formoterol (eformoterol) fumarate dihydrate.

Inactive ingredients:

  • sodium cromoglycate
  • absolute ethanol
  • apaflurane (HFA 227, propellant).

HFA 227 is a CFC-free propellant.

This medicine does not contain lactose, sucrose, gluten or tartrazine.

Supplier

FLUTIFORM® pressurised inhalation is supplied in Australia by:

Mundipharma Pty Limited
ABN 87 081 322 509
88 Phillip Street
Sydney, NSW, 2000
Phone: 1800 188 009

® FLUTIFORM is a registered trade mark of Jagotec AG used under licence by Mundipharma Pty Limited.

This leaflet was updated in September 2019.

Australian Registration Numbers for FLUTIFORM® pressurised inhalation:

50 micrograms/5 micrograms: AUST R 177869

125 micrograms/5 micrograms: AUST R 177873

250 micrograms/10 micrograms: AUST R 177875

RA-0275-001

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Flutiform

Active ingredient

Fluticasone propionate; Formoterol (eformoterol) fumarate dihydrate

Schedule

S4

 

1 Name of Medicine

Fluticasone propionate and eformoterol fumarate dihydrate.

6.7 Physicochemical Properties

Fluticasone propionate.

The chemical name is S-fluoromethyl 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyl-oxy-androsta-1, 4-diene-17β-carbothioate. The molecular formula is C25H31F3O5S.

Chemical structure.


CAS number.

80474-14-2.

Eformoterol fumarate dihydrate.

The chemical name is (±)-2'-hydroxy-5'-[(RS)]-1-hydroxy-2-[[(RS)-p-methoxy-α-methylphenethyl]amino]ethyl] formanilide fumarate dihydrate. The molecular formula is (C19H24N2O4)2.C4H4O4.2H2O.

Chemical structure.


CAS number.

43229-80-7.

2 Qualitative and Quantitative Composition

Fluticasone propionate.

It is a white to almost white powder, practically insoluble in water, slightly soluble in alcohol and sparingly soluble in dichloromethane.

Eformoterol fumarate dihydrate.

It is a white to almost white or yellowish powder. It is slightly soluble in water, sparingly soluble in isopropyl alcohol, soluble in methanol and practically insoluble in acetonitrile.

Flutiform inhaler.

Flutiform pressurised inhalation ('inhaler') is a white to off white liquid suspension inside a pressurised metal canister. The inactive ingredients are sodium cromoglycate, absolute ethanol and apaflurane (HFA 227). The active ingredients delivered by each metered dose from the canister valve are given in Table 1.

3 Pharmaceutical Form

Flutiform pressurised inhalation is contained in an aluminium pressurised canister crimped with a standard metering valve. The canister is inserted into a press-and-breathe actuator fitted with a dust cap, and an integrated dose indicator which indicates the number of doses remaining. The assembled inhaler is pouched in an aluminium foil laminate, and then packed in a cardboard carton.
The strengths of Flutiform pressurised inhalation are:
50 micrograms fluticasone propionate/5 micrograms eformoterol fumarate dihydrate;
125 micrograms fluticasone propionate/5 micrograms eformoterol fumarate dihydrate;
250 micrograms fluticasone propionate/10 micrograms eformoterol fumarate dihydrate.
Each container for the three strengths delivers 120 actuations.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fluticasone propionate is a synthetic trifluorinated glucocorticoid with potent anti-inflammatory activity in the lungs when administered by inhalation. Fluticasone propionate reduces the symptoms, improves lung function and prevents exacerbations of asthma, with fewer adverse effects than when corticosteroids are administered systemically. The use of an inhaled steroid improves symptomatic control of asthma, should reduce the need for short acting bronchodilators and may limit the reduction in lung function over time.
Eformoterol fumarate is a potent long-acting, selective β2-adrenergic receptor agonist. Inhaled eformoterol fumarate acts locally in the lungs as a bronchodilator, which provides symptomatic relief. After a single dose, onset of bronchodilation occurs rapidly within 1-3 minutes, with a duration of effect of at least 12 hours.
Flutiform inhaler belongs to the pharmacotherapeutic group 'adrenergics and other drugs for obstructive airway diseases' (ATC code: R03AK07). As with other combinations of inhaled corticosteroids and long acting β2-adrenergic agonists, the additive effect produces a reduction in the exacerbation of asthma.

Clinical trials.

Summary of clinical trials.

Studies to compare Flutiform inhaler with combination treatments (i.e. fluticasone plus eformoterol, or Seretide inhaler consisting of fluticasone plus salmeterol), or with its individual components administered separately, or administered with and without a spacer were conducted. Four of these studies were randomised, double blind, parallel group, stratified and active comparator controlled studies, two of which included a placebo control. A dose response relationship for Flutiform was not demonstrated for subjects with moderate to severe asthma.

Phase 3 studies.

1. Flutiform inhaler vs. concurrent therapy (combination fluticasone and eformoterol).

In study FLT3503, two strengths of Flutiform inhalers, 2 x 50/5 and 2 x 250/10 micrograms, were compared with combination therapy fluticasone 2 x 250 micrograms + eformoterol 2 x 12 micrograms, and with fluticasone 2 x 250 micrograms. Each treatment was taken twice daily. This randomised, double blind, parallel group, active controlled study was 8 weeks in duration, and enrolled 620 patients: 155 on Flutiform inhaler lower dose, 154 on Flutiform inhaler higher dose, 156 on fluticasone + eformoterol and 155 on fluticasone alone.
The primary objective was to show noninferiority in the efficacy of Flutiform inhaler vs. fluticasone and eformoterol administered concurrently in adult patients with moderate to severe, persistent asthma (FEV1 ≥ 40% to ≤ 80% for predicted normal values). Two secondary objectives were to show superiority in the efficacy of Flutiform inhaler high dose vs. fluticasone alone, and to show superiority in the efficacy of Flutiform inhaler high dose vs. Flutiform inhaler low dose. The primary efficacy endpoint was the mean change in pre-morning dose FEV1 from baseline to the end of treatment. The coprimary endpoint was the mean change in FEV1 from pre-morning dose at baseline to 2 hour post-morning dose at the end of treatment.
The least squares mean (LS mean) change in pre-morning dose FEV1 from baseline to end of treatment was 0.345 L in the Flutiform inhaler high dose group and 0.284 L in the fluticasone + eformoterol group. The treatment difference was 0.060 L (95% CI: -0.059 to 0.180). The LS mean change in FEV1 from premorning dose at baseline to 2 hour postmorning dose at the end of treatment was 0.518 L in the Flutiform inhaler high dose group and 0.500 L in the fluticasone + eformoterol group. The treatment difference was 0.018 L (95% CI: -0.098 to 0.135). Noninferiority of Flutiform inhaler high dose to fluticasone + eformoterol was demonstrated for both coprimary endpoints, as the lower limit of the 95% CI for the treatment difference exceeded the noninferiority acceptance limit of -0.2 L (p < 0.001).
All secondary spirometric and symptom based endpoints demonstrated no statistically significant or clinically relevant differences between Flutiform inhaler high dose and fluticasone + eformoterol. This study was not designed to assess the relative efficacy of high and low dose Flutiform however differences in mean change from baseline FEV1 at the end of treatment in subjects taking low dose Flutiform were similar to those achieved in subjects taking high dose Flutiform.
Symptom related endpoints indicated a dose-response trend.

2. Flutiform inhaler vs. fluticasone or eformoterol alone.

Three pivotal randomised, double blind, active controlled, parallel group, studies, two of which were also placebo controlled, were conducted to compare Flutiform inhaler with its individual components administered separately. The primary objective of each study was to demonstrate the efficacy of Flutiform inhaler compared with fluticasone and eformoterol alone and placebo when administered over 12 weeks.
Flutiform inhaler 2 x 50/5 micrograms was compared with fluticasone 2 x 50 micrograms, eformoterol 2 x 5 micrograms and placebo. All treatments were taken twice daily. The study enrolled a total of 475 adolescents and adult subjects with mild to moderate asthma. The number of subjects randomised to each group was 118, 119, 120 and 118, respectively. The three coprimary endpoints were: mean change in FEV1 from morning predose at baseline to predose at week 12 (to determine efficacy vs. fluticasone alone), the mean change in FEV1 from predose at baseline to 2 hours postdose at week 12 (to determine efficacy vs. eformoterol alone) and discontinuations due to lack of efficacy (to determine efficacy vs. placebo). Flutiform was superior to each of its comparators for each of the coprimary endpoints. The LS mean difference in mean change in FEV1 from morning predose at baseline to predose at week 12 was -0.101 L (95% CI: 0.002 to 0.199; p = 0.045). The LS mean difference in mean change in FEV1 from morning predose at baseline to 2 hours postdose at week 12 was -0.200 L (95% CI: 0.109 to 0.292; p < 0.001). 7 (6.1%) subjects given Flutiform, 9 (7.7%) given fluticasone, 13 (11.2%) given eformoterol and 18 (16.2%) given placebo discontinued prematurely due to lack of efficacy.
Flutiform inhaler 2 x 50/5 micrograms was compared with fluticasone 2 x 50 micrograms and eformoterol 2 x 5 micrograms. All treatments were taken twice daily. The study enrolled a total of 357 adolescents and adult subjects with mild to moderate asthma. The number of subjects randomised to each group was 119, 119 and 119, respectively. The two coprimary endpoints were: mean change in FEV1 from morning predose at baseline to predose at week 12 (to determine efficacy vs. fluticasone alone) and the mean change in FEV1 from predose at baseline to 2 hours postdose at week 12 (to determine efficacy vs. eformoterol alone). Flutiform was superior to each of its comparators for each of the coprimary endpoints. The LS mean difference in mean change in FEV1 from morning predose at baseline to predose at week 12 was 0.118 L (95% CI: 0.034 to 0.201; p = 0.006). The LS mean difference in mean change in FEV1 from morning predose at baseline to 2 hours postdose at week 12 was 0.122 L (95% CI: 0.040 to 0.204; p = 0.004).
In SKY2028-3-004, Flutiform inhaler 2 x 50/5 and 2 x 125/5 micrograms were compared with fluticasone 2 x 125 micrograms, eformoterol 2 x 5 micrograms and placebo. All treatments were taken twice daily. The study enrolled a total of 557 adolescents and adult subjects with mild to moderate asthma. The number of subjects randomised to each group was 110, 114, 113, 111 and 109, respectively.
The three co-primary endpoints were for the comparison of the 250/10 dose group to its components and to placebo. These endpoints were: mean change in FEV1 from morning predose at baseline to predose at week 12 (to determine efficacy vs. fluticasone alone), the mean change in FEV1 from predose at baseline to 2 hours post-dose at week 12 (to determine efficacy vs. eformoterol alone) and discontinuations due to lack of efficacy (to determine efficacy vs. placebo). Flutiform 250/10 was superior to each of its comparators for each of the coprimary endpoints.
The LS mean difference in mean change in FEV1 from morning predose at baseline to predose at week 12 was -0.189 L (p < 0.001). The LS mean difference in mean change in FEV1 from morning predose at baseline to 2 hours postdose at week 12 was -0.146 L (p = 0.006).
The number of subjects who discontinued prematurely due to lack of efficacy was 11 (10.2%) for Flutiform 250/10, 14 (12.8%) for fluticasone, 23 (20.9%) for eformoterol and 41 (39.0%) for placebo groups. This study was not designed to compare efficacy of the two Flutiform doses (250/10 and 100/10), however Flutiform 100/10 appeared to show similar results to the 250/10 dose.

3. Long-term efficacy.

Efficacy was assessed as a secondary objective in a long-term, open label safety study (SKY2028-3-003). Subjects were assigned to a 6 or 12 month treatment duration subset. The change from baseline to each visit in predose and postdose FEV1, FEV1% predicted, forced vital capacity (FVC) and peak expiratory flow rate (PEFR) was summarised for the two subsets, and changes within each dose group were analysed using the paired t-test.
Clinically important improvements at the α = 0.001 level were observed for all the efficacy assessments for Flutiform inhaler treatment overall and for each dose group (100/10 and 250/10 micrograms) at every assessment time point. These included: (i) the mean changes from baseline to predose assessment at week 2, at week 4, monthly thereafter and at the final visit; (ii) the mean changes from baseline to the 1 hour postdose assessment at week 2, week 4, month 2 and month 3; and (iii) the improved mean predose FEV1 values for both Flutiform inhaler doses, that were sustained throughout the 12 month treatment period.
The data presented in Figure 1 represents that from 175 patients who had data available at month 1 and month 12. These data demonstrate that predose FEV1 improved over the first 4 weeks and was then sustained over the entire 12 months treatment period for subjects who continued in this study.

5.2 Pharmacokinetic Properties

Fluticasone propionate.

Pharmacokinetic data are available for the inhalation and intravenous administration routes.

Absorption.

Following inhalation, systemic absorption of fluticasone propionate occurs mainly through the lungs. Absorption is initially rapid then prolonged. Published studies using oral dosing of labelled and unlabelled drug have demonstrated that the absolute oral systemic bioavailability of fluticasone propionate is negligible (< 1%), due to a combination of incomplete absorption from the gastrointestinal tract and extensive first-pass metabolism.

Distribution.

Following intravenous administration, fluticasone propionate is extensively distributed in the body. The initial disposition phase for fluticasone propionate is rapid, consistent with its high lipid solubility and tissue binding. The volume of distribution averages 4.2 L/kg. The percentage of fluticasone propionate bound to human plasma proteins averages approximately 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes.

Metabolism.

The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The very high clearance rate indicates an extensive hepatic clearance. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 isoform subfamily (CYP3A4) pathway. This metabolite has only very weak affinity for the glucocorticoid receptor of human lung cytosol in vitro.

Excretion.

87-100% of an oral dose is excreted in the faeces, up to 75% as parent compound. There is also a non-active major metabolite. Following intravenous dosing, fluticasone propionate shows polyexponential kinetics and has a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabelled dose is excreted in the urine as metabolites, and the remainder is excreted in the faeces as parent drug and metabolites.

Eformoterol fumarate.

Pharmacokinetic data are available for inhalation of therapeutic dosages in chronic obstructive pulmonary disease (COPD) patients, for inhalation of higher than recommended dosages in healthy volunteers, and for oral administration in healthy volunteers.

Absorption.

Following inhalation of a single 120 microgram dose of eformoterol fumarate by healthy volunteers, eformoterol was rapidly absorbed into plasma, reaching a maximum concentration of 91.6 picograms/mL within 5 minutes of inhalation. In COPD patients treated for 12 weeks with eformoterol fumarate 12 or 24 micrograms twice daily, the plasma concentrations of eformoterol ranged between 4.0 and 8.9 picograms/mL and 8.0 and 17.3 picogram/mL respectively at 10 minutes, at 2 hours and 6 hours post-inhalation.
In studies investigating the cumulative urinary excretion of eformoterol and/or its (RR) and (SS)-enantiomers, absorption increased linearly with the dose after inhalation of 12-96 micrograms of dry powder or aerosol formulations. After 12 weeks administration of 12 or 24 micrograms eformoterol powder twice daily, the urinary excretion of unchanged eformoterol increased by 63-73% in adult patients with asthma, by 19-38% in adult patients with COPD and by 18-84% in children. These results suggested a modest and self limiting accumulation of eformoterol in plasma after repeated dosing.
As reported for other inhaled drugs, it is likely that about 90% of eformoterol administered from an inhaler will be swallowed and then absorbed from the gastrointestinal tract. This means that the pharmacokinetic characteristics of the oral formulation largely apply to the inhalation powder. When 80 micrograms of 3H-labelled eformoterol fumarate was orally administered to two healthy volunteers, at least 65% of the drug was absorbed.

Distribution.

The plasma protein binding of eformoterol is 61-64% (34% primarily to albumin). There is no saturation of binding sites in the concentration range reached with therapeutic doses. The concentrations of eformoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 120 micrograms dose.

Metabolism.

Eformoterol is eliminated primarily by metabolism, direct glucuronidation being the major pathway of biotransformation, with O-demethylation followed by further glucuronidation being another pathway. Minor pathways involve sulphate conjugation of eformoterol and deformylation followed by sulphate conjugation. Multiple isozymes catalyse the glucuronidation (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7 and 2B15) and O-demethylation (CYP2D6, 2C19, 2C9 and 2A6) of eformoterol, and consequently the potential for metabolic drug-drug interaction is low. Eformoterol did not inhibit cytochrome P450 isozymes at therapeutically relevant concentrations. The kinetics of eformoterol is similar after single and repeated administration, indicating no autoinduction or inhibition of metabolism.

Excretion.

In asthmatic and COPD patients treated for 12 weeks with 12 or 24 micrograms eformoterol fumarate twice daily approximately 10% and 7% of the dose, respectively, were recovered in the urine as unchanged eformoterol. In asthmatic children, approximately 6% of the dose was recovered in the urine as unchanged eformoterol after multiple dosing of 12 and 24 micrograms. The (R, R) and (S, S)-enantiomers accounted for 40% and 60% respectively of urinary recovery of unchanged eformoterol, after single doses (12 to 120 micrograms) in healthy volunteers, and after single and repeated doses in asthma patients. After a single oral dose of 3H-eformoterol, 59-62% of the dose was recovered in the urine and 32-34% in the faeces. Renal clearance of eformoterol is 150 mL/min.
After inhalation, plasma eformoterol kinetics and urinary excretion rate data in healthy volunteers indicate a biphasic elimination, with the terminal elimination half-lives of the (R,R) and (S,S)-enantiomers being 13.9 and 12.3 hours, respectively. Peak excretion occurs within 1.5 hours. Approximately 6.4-8% of the dose was recovered in the urine as unchanged eformoterol, with the (R,R) and (S,S)-enantiomers contributing 40% and 60%, respectively.

Fluticasone propionate/ eformoterol fumarate in combination.

A number of studies have examined the pharmacokinetic characteristics of fluticasone propionate and eformoterol fumarate in Flutiform inhaler compared with the individual components, administered together and separately. There is a high variability both within and between the pharmacokinetic studies, however, in general there is a trend for the systemic exposure of fluticasone and eformoterol to be less with Flutiform inhaler than with the individual components administered together.

Absorption.

Flutiform inhaler (fluticasone propionate): following inhalation of a single 250 micrograms dose of fluticasone propionate from 2 actuations of Flutiform inhaler 125 micrograms/5 micrograms by healthy volunteers, fluticasone propionate was rapidly absorbed into the plasma, reaching a mean maximum plasma fluticasone concentration of 32.8 picograms/mL within 45 minutes of inhalation. In asthma patients who received single doses of fluticasone propionate from Flutiform inhaler, mean maximum plasma concentrations of 15.4 picograms/mL and 27.4 picograms/mL were achieved within 20 minutes and 30 minutes for 100 micrograms/10 micrograms (2 actuations of Flutiform inhaler 50 micrograms/5 micrograms) and 250 micrograms/10 micrograms (2 actuations of Flutiform inhaler 125 micrograms/5 micrograms) doses, respectively.
In multiple dose studies in healthy volunteers, Flutiform inhaler doses of 100 micrograms/10 micrograms, 250 micrograms/10 micrograms and 500 micrograms/20 micrograms resulted in mean maximum plasma fluticasone concentrations of 21.4, 25.9 to 34.2 and 178 picograms/mL, respectively. The data for the 100 micrograms/10 micrograms and 250 micrograms/10 micrograms doses were generated by the use of a device without a spacer, and the data for the 500 microgram/20 microgram dose were generated by the use of a device with a spacer. Although there are no data directly comparing the exposure of fluticasone from a device with or without a spacer, spacers are known to increase the systemic exposure of fluticasone, and this may account for some of the difference in the levels achieved between the different doses.
Flutiform inhaler (eformoterol fumarate): following a single dose of Flutiform inhaler in healthy volunteers, a dose of 20 micrograms of eformoterol fumarate from 2 actuations of Flutiform inhaler 250 micrograms/10 micrograms resulted in a mean maximum plasma eformoterol concentration of 9.92 picograms/mL within 6 minutes of inhalation. Following multiple doses, 20 micrograms of eformoterol fumarate from 2 actuations of Flutiform inhaler 250 micrograms/10 microgram resulted in a mean maximum plasma eformoterol concentration of 34.4 picograms/mL.

Excretion.

Following the inhalation of fluticasone propionate from 2 actuations of Flutiform inhaler 250 micrograms/10 micrograms, fluticasone propionate has a terminal elimination half-life of approximately 14.2 hours.
Following the inhalation of eformoterol fumarate from 2 actuations of Flutiform inhaler 250 micrograms/10 micrograms, eformoterol fumarate has a terminal elimination half-life of approximately 6.5 hours. Less than 2% of a single dose of eformoterol fumarate from Flutiform inhaler is excreted in the urine.

5.3 Preclinical Safety Data

Genotoxicity.

The potential genotoxicity of fluticasone propionate and eformoterol fumarate in combination has not been studied. Individually, the two agents exhibited no mutagenic or clastogenic effects in a battery of in vitro and in vivo tests.

Carcinogenicity.

No carcinogenic studies with fluticasone propionate and eformoterol fumarate in combination have been conducted. Long-term rodent studies have been performed with the individual active components.

Fluticasone propionate.

No evidence of tumourigenic activity was observed with fluticasone propionate in an 18 month study in mice treated at oral doses up to 1,000 micrograms/kg (approximately 5 times the MRHD in adults and children, on a micrograms/m2 basis) or in a 2 year study in rats given doses up to 57 micrograms/kg (less than the MRHD in adults and children, on a micrograms/m2 basis).

Eformoterol fumarate.

In 2 year studies in mice and rats, treatment with eformoterol fumarate, given via the diet or drinking water at very high doses, was associated with increases in several tumour types. In mice, these included hepatocellular adenoma and carcinomas (≥ 2 mg/kg/day), leiomyomas and leiomyosarcomas in the female reproductive tract (≥ 2 mg/kg/day) and adrenal subcapsular cell tumours (≥ 66 mg/kg/day). In rats, treatment was associated with benign granulosa/ theca cell tumours in the ovaries (≥ 0.5 mg/kg/day), mesovarian leiomyomas (≥ 18 mg/kg/day), mammary adenocarcinomas (≥ 36 mg/kg/day) and thyroid C-cell neoplasms (46 mg/kg/day). A mesovarian leiomyoma was also observed in a female rat dosed by inhalation at 130 micrograms/kg/day for two years (approximately 30-47 times the MRHD in adults and children on a micrograms/m2 basis). Mammary adenocarcinomas, smooth muscle tumours in the female reproductive tract and effects on the ovary have been reported in rats and mice treated with other β2-adrenoreceptor agonists and are likely to be secondary to prolonged stimulation of β2-adrenoreceptors in these tissues.

4 Clinical Particulars

4.1 Therapeutic Indications

Flutiform inhaler is indicated for the regular maintenance treatment of asthma where the use of a combination product (an inhaled corticosteroid and a long acting β2-agonist) is appropriate. This includes patients not adequately controlled with inhaled corticosteroids and inhaled short acting β2-agonist on an 'as required' basis.

4.3 Contraindications

Flutiform inhaler is contraindicated in patients with hypersensitivity to any of the active substances or to the excipients.

4.4 Special Warnings and Precautions for Use

Treatment guidelines.

Flutiform inhaler should not be used as the first treatment for asthma. It is indicated for adolescents over 12 years and adults over 18 years. The management of asthma should normally follow a stepwise programme and patients' responses should be monitored clinically and with lung function tests.
Flutiform inhaler should not be used to treat acute asthma symptoms, for which a fast and short acting bronchodilator is required. Flutiform inhaler should not be used to transfer patients from oral to inhaled corticosteroids. Patients should be advised to have their medicine available at all times for relief during an acute asthma attack.
Patients should not be initiated on Flutiform inhaler during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma. Serious asthma-related adverse events and exacerbations may occur during treatment with Flutiform inhaler. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Flutiform inhaler.
Increasing use of short acting bronchodilators to relieve asthma symptoms indicates a deterioration of asthma control, and these patients should be reviewed by a physician. Sudden and progressive deterioration in the control of asthma is potentially life threatening and these patients require urgent medical assessment. Patients should be medically reviewed when their current dosage of Flutiform fails to give adequate control of asthma. Consideration should be given to either increasing, or to additional corticosteroid therapies. The lowest effective dose of Flutiform inhaler should be used. Treatment with Flutiform should not be stopped abruptly in patients with asthma, due to risk of exacerbation. Therapy should be down titrated under the supervision of a physician.

To avoid overtreatment and unnecessary adverse effects.

Initiate therapy with sufficient medication to achieve best lung function promptly after about 3 months of good control (which is characterised by few symptoms, minimal use of short acting β2 agonists, and no exercise limitation), reduce inhaled corticosteroids to the minimum dose needed to maintain adequate asthma control ('stepping down').
Consider seasonal adjustment of doses as the minimum required dose may vary.

Precautions for use.

Flutiform should not be used more often than recommended, at higher doses than recommended or in combination with other medications containing long acting β2-agonists as an overdose may result.
As with all inhaled medication containing corticosteroids, Flutiform inhaler should be administered with caution in patients with active or quiescent pulmonary tuberculosis, untreated systemic infections, ocular herpes simplex or patients with fungal, viral or other infections of the airway. Any such infections must always be adequately treated if Flutiform inhaler is being used.
An exacerbation of the clinical symptoms of asthma may be due to acute respiratory tract bacterial infection and treatment may require appropriate antibiotics, increased inhaled corticosteroids and a short course of oral corticosteroids. A rapid-acting inhaled bronchodilator should be used as rescue medication.
The prophylactic use of Flutiform inhaler in exercise induced asthma has not been studied. For such use, a separate rapid acting bronchodilator should be considered.

Cardiovascular effects.

Cardiovascular effects such as increases in systolic blood pressure and heart rate, may occasionally be seen with all sympathomimetic drugs, especially at higher than therapeutic doses. For this reason, Flutiform should be used with caution in patients with pre-existing cardiovascular disease including prolongation of the QTc interval. Eformoterol itself may induce prolongation of the QTc interval.
A transient decrease in serum potassium may occur with all sympathomimetic drugs at higher therapeutic doses.
Flutiform should be used with caution in patients with a history of thyrotoxicosis, phaeochromocytoma, diabetes mellitus, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischaemic heart disease, cardiac arrhythmias or severe heart failure.
As for all β2-agonists, additional blood sugar controls should be considered for diabetic patients.
Potentially serious hypokalaemia may result from high doses of β2-agonists. Concomitant treatment of β2-agonists with drugs which can induce or potentiate a hypokalaemic effect, e.g. xanthine derivatives, steroids and diuretics, may add to a possible hypokalaemic effect of the β2-agonist. Particular caution is recommended in unstable asthma with variable use of rescue bronchodilators, in acute severe asthma as the associated risk may be augmented by hypoxia and in other conditions when the likelihood for hypokalaemia adverse effects is increased. It is recommended that serum potassium levels are monitored during these circumstances.
Care should be taken when transferring patients to Flutiform inhaler therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy.
As with other inhalation therapy paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. Flutiform inhaler should be discontinued immediately, the patient assessed and alternative therapy instituted if required.

Possible systemic effects, including adrenocortical function, bone density and growth.

Inhaled steroids are designed to direct glucocorticoid delivery to the lungs in order to reduce overall systemic glucocorticoid exposure and side effects. With sufficient doses however, all inhaled steroids can have adverse effects; possible systemic effects include Cushing's syndrome, Cushingoid features, depression of the hypothalamic-pituitary adrenal (HPA) axis, reduction of bone mineral density, cataract, glaucoma and retardation of growth rate in children and adolescents. More rarely, psychological or behavioural effects have included psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression, particularly in children (see Section 4.9 Overdose).
The lowest dose of inhaled fluticasone that causes suppression of the HPA axis (as indicated by the 24 hour urinary cortisol concentrations), effects on bone mineral density or growth retardation in children has not yet been established. Some depression of plasma cortisol may occur in a small number of adult patients on higher doses (e.g. > 1 mg/day). In situations of possible impaired adrenal function, HPA axis function should be monitored regularly. Adrenal function and adrenal reserve usually remain within normal range on inhaled fluticasone propionate therapy. However, prolonged treatment with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis.
Data regarding the effect of long-term use of inhaled fluticasone on bone mineral density in elderly patients are limited.
Patients in a medical or surgical emergency, who in the past have required high doses of inhaled steroids and/or intermittent treatment with oral steroids, remain at risk of impaired adrenal reserve for a considerable time. The extent of the adrenal impairment may require specialist advice before elective procedures. The possibility of residual impaired adrenal response should always be borne in mind in emergency and elective situations likely to produce stress and appropriate corticosteroid treatment must be considered (see Section 4.8 Adverse Effects (Undesirable Effects)).
In rare cases, inhaled therapy may unmask underlying eosinophilic conditions (e.g. Churg Strauss syndrome). These cases have usually been associated with reduction or withdrawal of oral corticosteroid therapy. A direct causal relationship has not been established.
Additional systemic corticosteroid treatment should be considered during periods of stress or elective surgery.

Spacer devices.

Most patients will benefit from the consistent use of a spacer device with their metered dose inhaler (MDI or puffer), particularly those with poor inhaler technique. Use of a spacer will also decrease the amount of drug deposited in the mouth and back of the throat, and therefore reduce the incidence of local side effects such as 'thrush' and a hoarse voice.
A change in the make of spacer may be associated with alterations in the amount of drug delivered to the lungs. The clinical significance of these alterations is uncertain. However, in these situations, the person should be monitored for any loss of asthma control.
If using a spacer, the patient should be instructed to actuate the inhaler into the spacer and then slowly breathe in as far as possible. Hold your breath for as long as comfortable, before breathing out slowly. This should be repeated for each actuation of the drug into the spacer. Any delays between actuation and inhalation should be kept to a minimum.
Static on the walls of the spacer may cause variability in drug delivery. Patients should be instructed to wash the spacer in warm water and detergent and allow it to air dry without rinsing or drying with a cloth. This should be performed before initial use of the spacer and at least monthly thereafter.

Visual disturbance.

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, 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) which have been reported after use of systemic and topical corticosteroids.

Use in hepatic impairment.

As the fractions of fluticasone and eformoterol which reach systemic circulation are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe hepatic impairment.
No data is available on the use of Flutiform inhaler in patients with hepatic impairment.

Use in renal impairment.

No data is available on the use of Flutiform inhaler in patients with renal impairment.

Use in the elderly.

There is no need to adjust the dose in elderly patients.

Paediatric use.

The safety and efficacy of Flutiform inhaler have not been assessed in children under 12 years of age. Therefore, Flutiform inhaler is not recommended for children under 12 years.

Effects on laboratory tests.

A transient decrease in serum potassium may occur with all sympathomimetic drugs (eformoterol component of Flutiform) at higher therapeutic doses.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug interaction studies have been performed with Flutiform inhaler.

CYP34A inhibitors.

There is an increased risk of systemic side effects when combining fluticasone propionate with potent CYP3A4 inhibitors. Fluticasone propionate, an individual component of Flutiform inhaler, is a substrate of CYP3A4. Caution needs to be taken in long-term treatment of co-medication of strong CYP3A4 inhibitors (e.g. ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nelfinavir, saquinavir, ketoconazole, telithromycin, cobicistat) together with Flutiform inhaler and coadministration with such drugs should be avoided if possible. Particularly comedication of ritonavir should be avoided unless the benefit outweighs the increased risks. Information about this interaction is lacking for inhaled fluticasone propionate, but a marked increase in fluticasone propionate plasma levels is expected. Cases of Cushing's syndrome and adrenal suppression have been reported.

Non-potassium sparing diuretics.

The ECG changes and/or hypokalaemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by β-agonists, especially when the recommended dose of the β-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of a β-agonist with nonpotassium sparing diuretics.

Xanthine derivatives and glucocorticosteroids.

Xanthine derivatives and glucocorticosteroids may add to the possible hypokalaemic effect of β-agonists discussed above.

Digitalis glycosides.

Hypokalaemia may increase the risk of arrhythmias in patients who are treated with digitalis glycosides.

Halogenated hydrocarbon anaesthetics.

There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.

Monoamine oxidase inhibitors.

Concomitant treatment with monoamine oxidase inhibitors (MAOIs), including agents with similar properties such as furazolidone and procarbazine, may precipitate hypertensive reactions.

Drugs known to prolong QTc interval.

Eformoterol fumarate, as with other β2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants (or within two weeks of their discontinuation), or drugs known to prolong the electrocardiographic QTc interval such as quinidine, disopyramide, procainamide, phenothiazines and antihistamines. Drugs that are known to prolong the QTc interval increase the risk of ventricular arrhythmias.

Adrenergic drugs.

If additional adrenergic drugs are to be administered by any route, they should be used with caution, because the pharmacologically predictable sympathetic effects of eformoterol may be potentiated. Concomitant use of β-adrenergic drugs can have a potentially additive effect.

β-Blockers.

Beta-adrenergic receptor antagonists (β-blockers) and eformoterol fumarate may inhibit the effect of each other when administered concurrently. β-Blockers may also produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with β-blockers and this includes β-blockers used as eye drops for treatment of glaucoma. However, under certain circumstances, e.g. as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of β-blockers in patients with asthma. In this setting, cardioselective β-blockers could be considered, although they should be administered with caution.

L-dopa, L-thyroxine, oxytocin and alcohol.

L-dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards β2 sympathomimetics.

Sodium cromoglycate.

Flutiform inhaler contains sodium cromoglycate at non-pharmacological levels. Patients should not discontinue any cromoglycate containing medication.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No animal studies have been conducted with fluticasone propionate and eformoterol fumarate in combination to evaluate effects on fertility. Studies in rats with the individual active components showed no evidence of impairment of fertility with fluticasone propionate at subcutaneous doses up to 50 micrograms/kg/day (approximately half the maximum recommended human dose [MRHD] on a microgram/m2 body surface area basis), nor with eformoterol fumarate at oral doses up to 60 mg/kg/day.
(Category B3)
There are no adequate and well-controlled studies with Flutiform inhaler in pregnant or breastfeeding women. There are only limited data in pregnant women on the use of Flutiform inhaler, and on the use of fluticasone propionate inhaler and eformoterol fumarate inhaler, administered alone or together. Studies in animals have shown reproductive toxicity. In pregnant rabbits, treatment with fluticasone propionate and eformoterol fumarate in combination by inhalation during the period of organogenesis (doses of 2/0.2 to 40/4 micrograms/kg/day fluticasone propionate/ eformoterol fumarate) caused serious adverse effects on embryofetal development including increased post-implantation loss and malformations (cleft palate). These occurred in the absence of maternotoxicity and at doses yielding exposure to the two drugs (plasma and AUC) less than that expected in patients at MRHD. Decreased fetal weight and increased incidences of fetal skeletal variations and retarded ossification were observed in a corresponding study in rats in which treatment (doses up to 160/16 micrograms/kg/day fluticasone propionate/ eformoterol fumarate) yielded drug exposure up to four times (fluticasone propionate) or six times (eformoterol fumarate) the clinical AUC at the MRHD. These findings are compatible with those of previous studies conducted with the individual drugs. Corticosteroids are known to induce fetotoxicity and teratogenicity in animals, but these results may not be relevant to human therapy. Administration of Flutiform inhaler is not recommended during pregnancy, and should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus. Because of the potential for beta-agonist interference with uterine contractility, use of Flutiform inhaler for the management of asthma during labour should be restricted to those patients in whom the benefit outweighs the risks, and the lowest effective dose to maintain adequate asthma control should be used.
It is not known whether fluticasone propionate or eformoterol fumarate, or their metabolites, are excreted in human breast milk. Such excretion has been demonstrated for both drugs in lactating rats. In addition, growth and survival of pups were found to be decreased when lactating rats were given eformoterol fumarate at oral doses greater than 1 mg/kg/day. A risk to the suckling child cannot be excluded. Therefore, the administration of Flutiform to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

4.8 Adverse Effects (Undesirable Effects)

Adverse effects with fluticasone propionate and eformoterol in Flutiform inhaler are listed by system organ class (SOC), in order of decreasing seriousness within each SOC in Table 2.
As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid acting inhaled bronchodilator and should be treated immediately. Inhalation therapy should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
The common adverse events reported for ≥ 1.0% of subjects in any treatment group in the pooled safety analysis are presented in Table 3. The adverse event profile was generally comparable amongst all the treatment groups, but the longer exposure time in the Flutiform inhaler group compared with other comparator groups could be expected to influence the rates.

Post marketing.

System organ class.

Eye disorders.

Adverse event.

Vision blurred.

Frequency.

Not known.

Patient exposure.

A total of 1,746 adult and adolescent patients with mild to severe asthma have been treated with Flutiform inhaler in clinical phase 3 studies. A pooled analysis of safety was conducted and the results from eight pooled phase 3 trials are presented in Tables 2 and 3. The studies were all 12 weeks in duration, apart from one study which was up to 52 weeks and one which was 8 weeks.
Additionally, a total of 337 subjects were treated with Flutiform inhaler in four phase 1 and phase 2 single dose studies, making a total of over 2,000 patients who have received at least one dose of Flutiform inhaler. No long-term studies beyond 12 weeks were conducted at the highest Flutiform dose (500/20 microgram).
Since Flutiform inhaler contains both fluticasone propionate and eformoterol fumarate, the same pattern of undesirable effects as reported for these substances may occur, as indicated below, although these have not been seen during the clinical development of Flutiform inhaler:

Fluticasone propionate.

Hypersensitivity reactions including urticaria, pruritus, angioedema (mainly facial and oropharyngeal), anaphylactic reactions. Systemic effects of inhaled corticosteroids may occur, particularly at high dosages prescribed for prolonged periods. These may include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma, sleep disorders, contusion, skin atrophy and susceptibility to infections. The ability to adapt to stress may be impaired. The systemic effects described, however, are much less likely to occur with inhaled corticosteroids than with oral corticosteroids. Prolonged treatment with high doses of inhaled corticosteroids may result in clinically significant adrenal suppression and acute adrenal crisis. Additional systemic corticosteroid cover may be required during periods of stress (trauma, surgery, infection).

Eformoterol fumarate.

Hypersenstivity reactions (including hypotension, angioneurotic oedema, pruritus, exanthema), QTc interval prolongation, hypokalaemia, nausea, myalgia, increased blood lactate levels. Treatment with β2-agonists such as eformoterol may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.
Hypersensitivity reactions have been reported in patients using inhaled sodium cromoglycate as an active ingredient. Whilst Flutiform inhaler contains only a low concentration of sodium cromoglycate as an excipient, it is unknown if hypersensitivity reactions are dose dependent.
In the unlikely event of a hypersensitivity reaction to Flutiform inhaler, treatment should be initiated in accordance with standard treatment for any other hypersensitivity reaction, which may include the use of antihistamines and other treatment as required. Flutiform inhaler may be discontinued immediately and an alternative asthma therapy may be initiated if necessary.
Dysphonia and candidiasis may be relieved by gargling or rinsing the mouth with water or brushing the teeth after using the product. Symptomatic candidiasis may be treated with topical antifungal therapy while continuing the treatment with Flutiform inhaler.

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

Flutiform inhaler is for administration by the inhaled route in patients with asthma from the age of 12 years and older. Flutiform inhaler is delivered by a press-and-breathe pressurised metered dose inhaler (pMDI) which also contains an integrated dose indicator. Each inhaler will provide at least 120 actuations (60 doses).
Patients will need to be trained on the use of the inhaler and should be regularly reassessed by a doctor, so that the strength of Flutiform inhaler they are receiving remains optimal and is only changed on medical advice. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. Patients should be regularly assessed by a doctor so the dose of Flutiform they are receiving remains optimal. Strength of dose should only be increased or decreased on medical advice.
Patients should be given the strength of Flutiform inhaler containing the appropriate fluticasone propionate dosage for the severity of their disease.

Note.

Flutiform inhaler 50 micrograms/5 micrograms strength is not appropriate in adults and adolescents with severe asthma. If an individual patient should require dosages outside the recommended regimen, appropriate doses of beta-agonist and/or corticosteroid in single inhalers should be prescribed.
The long-term efficacy of the highest dose of 500/20 micrograms (2 actuations of 250/10 micrograms) twice daily has not been evaluated. The efficacy and safety data for the highest dose are only available from the 8 week phase 3 study FLT3503 (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Recommended dose for adults and children aged 12 years and above.

Two inhalations of Flutiform inhaler 50/5 micrograms or Flutiform inhaler 125/5 micrograms twice daily. If the patient's asthma remains poorly controlled on Flutiform inhaler 50/5 micrograms, the total daily dose of the inhaled corticosteroid can be increased by administering the next highest strength combination product, i.e. Flutiform inhaler 125/5 micrograms, two puffs twice daily.

Recommended dose for adults only.

Two inhalations of Flutiform inhaler 250/10 micrograms twice daily. If the patient's asthma remains poorly controlled on Flutiform inhaler 125/5 micrograms, the total daily dose can be increased by administering the next highest strength combination product, i.e. Flutiform inhaler 250/10 micrograms, two puffs twice daily.

Children under 12 years.

Flutiform inhaler is not recommended for children under 12 years (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

Patients currently receiving medium to high doses of inhaled corticosteroids.

For patients who are currently receiving medium to high doses of inhaled corticosteroid therapy, and whose disease severity clearly warrants treatment with two maintenance therapies, the recommended starting dose is two inhalations twice daily of Flutiform inhaler 125/5 micrograms.

Special patient groups.

There is no need to adjust the dose in elderly patients.
There is no data available for use of Flutiform inhaler in patients with hepatic or renal impairment. These patients should be regularly monitored by a physician to ensure titration to the lowest dose at which effective control of symptoms is maintained. As the fractions of fluticasone and eformoterol which reach systemic circulation are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe hepatic impairment.

General information.

Patients should be made aware that Flutiform inhaler must be used daily for optimum benefit, even when asymptomatic. Patients using Flutiform inhaler should not use additional long acting β2-agonists for any reason. If asthma symptoms arise in the period between doses, an inhaled, short acting β2-agonist should be taken for immediate relief.
Each dose of Flutiform inhaler is administered as two inhalations twice daily (normally taken in the morning and the evening). The use of one actuation twice daily of Flutiform inhaler has not been investigated in clinical trials.
Patients should rinse their mouth, gargle with water or brush their teeth after inhaling and spit out the residue to minimise the risk of oral candidiasis or dysphonia.
Use of a spacer device with Flutiform inhaler is recommended in patients who find it difficult to synchronise aerosol actuation with inspiration of breath. The Aero Chamber Plus spacer device can be used.
Patients should be instructed in the proper use and care of their inhaler and spacer and their technique checked to ensure optimum delivery of the inhaled drug to the lungs. Retitration to the lowest effective dose should always follow the introduction of a spacer device.

Instruction for use.

To ensure proper administration of the drug, the patient should be shown how to use the inhaler correctly by a physician or other healthcare professionals. The correct use of the pressurised metered dose inhaler (pMDI) is essential for successful treatment. The patient should be advised to read the Consumer Medicine Information leaflet carefully and follow the instructions for use in the leaflet.

Priming the inhaler.

Before using the inhaler for the first time or if the inhaler has not been used for 3 days or more, the inhaler should be primed before use.
Remove the mouthpiece cover and shake the inhaler well.
Spray (away from the face). This step should be performed 4 times.
The inhaler should always be shaken immediately before use.
Whenever possible patients should stand or sit in an upright position when inhaling from the inhaler.
If the inhaler is exposed to freezing conditions, then the patient must be advised to allow the product to warm up at room temperature for 30 minutes, and then reprime the inhaler using two actuations.

Steps to follow for use of inhaler.

1. Remove the cap from the mouthpiece and check that the mouthpiece is clean, and free from dust and dirt. The inhaler should be shaken immediately before releasing each puff.
2. Breathe out as slowly and deeply as possible.
3. Hold the canister vertically with its body upwards and put the lips around the mouthpiece. Do not bite the mouthpiece.
4. At the same time, breathe in slowly and deeply through the mouth. After starting to breathe in, press down on the top of the inhaler to release one puff.
5. Hold the breath for as long as possible and, finally, remove the inhaler from the mouth and breathe out slowly. Do not breathe out into the inhaler.
6. Keep the inhaler in a vertical position for about half a minute, shake the inhaler, and repeat steps 2 to 5.
7. After use, replace the protective cap over the mouthpiece.

Important information.

Do not perform steps 2 to 5 too quickly.
If a mist appears following inhalation, either from the inhaler or from the sides of the mouth, the procedure should be repeated from step 2.
For patients with weak hands, it may be easier to hold the inhaler with both hands. Therefore the index fingers should be placed on the top of the inhaler canister and both thumbs on the base of the inhaler.
Patients should rinse their mouth, gargle with water or brush the teeth after inhaling and spit out the residue.

Cleaning.

Patients should be advised to read the Consumer Medicine Information leaflet carefully for cleaning instructions, and to clean their inhalers once a week, as follows:
Remove the mouthpiece cover.
Do not remove the canister from the plastic casing.
Wipe the inside and outside of the mouthpiece and the outside of the plastic casing with a dry cloth or tissue.
Replace the mouthpiece cover in the correct orientation.

Disposal.

The container should not be punctured, broken or burnt, even when apparently empty, as the canister contains a pressurised liquid. Apart from this, there are no special requirements for the disposal of Flutiform inhaler.

4.7 Effects on Ability to Drive and Use Machines

Flutiform inhaler is unlikely to have an effect on the ability to drive and operate machines. However, adverse effects of Flutiform include visual disturbances (such as blurred vision), dizziness, and vertigo which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.9 Overdose

There are no data available from clinical trials on overdose with Flutiform inhaler. Information on overdose by the single active components is provided below:

Fluticasone propionate.

Symptoms.

Acute inhalation of fluticasone propionate doses in excess of those recommended may lead to temporary suppression of hypothalamic pituitary adrenocortical (HPA) axis function. HPA axis function usually recovers in a few days, as verified by plasma cortisol measurements. Treatment with the inhaled corticosteroid should be continued at the recommended dose to control asthma.
There are reports on rare cases of acute adrenal crisis. Children and adolescents < 16 years taking high doses of fluticasone propionate: (typically ≥ 1000 microgram/day) may be at particular risk. Presenting symptoms are typically vague and may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting and hypotension. Typical symptoms of an adrenal crisis are decreased level of consciousness, hypoglycaemia and/or seizures.
Following chronic use of very high doses, a degree of atrophy of the adrenal cortex and HPA axis suppression may occur. Monitoring of adrenal reserve may be necessary. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma (see Section 4.4 Special Warnings and Precautions for Use).

Treatment.

In cases of fluticasone propionate overdose the dose of Flutiform inhaler should be tapered. In the management of chronic overdose, oral or systemic corticosteroids may be required in situations of stress. All patients deemed to be chronically overdosed should be treated as if steroid dependent with a suitable maintenance dose of a systemic corticosteroid. Therapy with Flutiform inhaler may still be continued at a suitable dosage for symptom control.

Eformoterol fumarate.

Symptoms.

An overdose of eformoterol would likely lead to an exaggeration of effects that are typical for β2-agonists, in which case the following adverse experiences may occur: angina, hypertension or hypotension, palpitations, tachycardia, arrhythmia, prolonged QTc interval, headache, tremor, nervousness, muscle cramps, dry mouth, insomnia, fatigue, malaise, seizures, metabolic acidosis, hypokalaemia, hyperglycaemia, nausea and vomiting.

Treatment.

Treatment of eformoterol overdosage consists of discontinuation of the medication together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective β-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial in cases of eformoterol overdose. Cardiac monitoring is recommended in cases of overdosage.
If Flutiform inhaler therapy has to be withdrawn due to overdose of the beta-agonist component, provision of appropriate replacement steroid therapy should be considered. Additionally, hypokalaemia can occur and potassium replacement should be considered.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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.

6.4 Special Precautions for Storage

Store below 25°C. Do not refrigerate or freeze.
Use within 3 months of opening the foil pouch, or until the dose indicator reads '0' (whichever comes first).

6.5 Nature and Contents of Container

Aerosol can-Metered dose/Al.

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