Consumer medicine information

Fluticasone Salmeterol Ciphaler 500/50

Fluticasone propionate; Salmeterol

BRAND INFORMATION

Brand name

Fluticasone Salmeterol Ciphaler 500/50

Active ingredient

Fluticasone propionate; Salmeterol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fluticasone Salmeterol Ciphaler 500/50.

SUMMARY CMI

FLUTICASONE SALMETEROL CIPHALER 500/50

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using FLUTICASONE SALMETEROL CIPHALER 500/50?

FLUTICASONE SALMETEROL CIPHALER 500/50 contains the active ingredients fluticasone propionate and salmeterol (as xinafoate). FLUTICASONE SALMETEROL CIPHALER 500/50 is used to help with asthma and chronic obstructive pulmonary disease (COPD) in people who need regular treatment.

For more information, see Section 1. Why am I using FLUTICASONE SALMETEROL CIPHALER 500/50? in the full CMI.

2. What should I know before I use FLUTICASONE SALMETEROL CIPHALER 500/50?

Do not use if you have ever had an allergic reaction to any medicine containing fluticasone propionate or salmeterol (as xinafoate) or lactose monohydrate or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use FLUTICASONE SALMETEROL CIPHALER 500/50? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with FLUTICASONE SALMETEROL CIPHALER 500/50 and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use FLUTICASONE SALMETEROL CIPHALER 500/50?

  • Follow dosage directions given to you by your doctor or pharmacist and continue taking it for as long as your doctor tells you.
  • FLUTICASONE SALMETEROL CIPHALER 500/50 should be inhaled into your lungs through the mouth, through the inhaler.

More instructions can be found in Section 4. How do I use FLUTICASONE SALMETEROL CIPHALER 500/50? in the full CMI.

5. What should I know while using FLUTICASONE SALMETEROL CIPHALER 500/50?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using FLUTICASONE SALMETEROL CIPHALER 500/50.
  • If you are going to have surgery, tell the surgeon or anesthetist that you are taking this medicine.
  • Tell your doctor if you become, or are trying to become, pregnant.
  • Tell your doctor if you are using FLUTICASONE SALMETEROL CIPHALER 500/50, if you have any blood tests.
  • Contact your doctor if you experience a change in your vision.
  • Keep all of your doctor's appointments so that your progress can be checked.
Things you should not do
  • Do not stop using this medicine suddenly or change the dosage without checking with your doctor.
Driving or using machines
  • This medicine is not expected to affect your ability to drive a car or operate machinery. It is prudent to be careful driving or operating machinery until you know how FLUTICASONE SALMETEROL CIPHALER 500/50 affects you.
Looking after your medicine
  • Keep FLUTICASONE SALMETEROL CIPHALER 500/50 in a dry place where the temperature stays below 30°C away from direct heat or sunlight.
  • Keep it where children cannot reach it.

For more information, see Section 5. What should I know while using FLUTICASONE SALMETEROL CIPHALER 500/50? in the full CMI.

6. Are there any side effects?

The following common side effects may occur when taking FLUTICASONE SALMETEROL CIPHALER 500/50; soreness in the mouth, throat or tongue, hoarseness, headache, muscle cramps, pain in joints, increase in heart rate, pneumonia. If your breathing or wheezing gets worse straight after using FLUTICASONE SALMETEROL CIPHALER 500/50, stop using it immediately and tell your doctor as soon as possible.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

FLUTICASONE SALMETEROL CIPHALER 500/50

Active ingredients: Fluticasone propionate/Salmeterol xinafoate

Consumer Medicine Information (CMI)

This leaflet provides important information about using FLUTICASONE SALMETEROL CIPHALER 500/50. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using FLUTICASONE SALMETEROL CIPHALER 500/50.

Where to find information in this leaflet:

1. Why am I using FLUTICASONE SALMETEROL CIPHALER 500/50?
2. What should I know before I use FLUTICASONE SALMETEROL CIPHALER 500/50?
3. What if I am taking other medicines?
4. How do I use FLUTICASONE SALMETEROL CIPHALER 500/50?
5. What should I know while using FLUTICASONE SALMETEROL CIPHALER 500/50?
6. Are there any side effects?
7. Product details

1. Why am I using FLUTICASONE SALMETEROL CIPHALER 500/50?

FLUTICASONE SALMETEROL CIPHALER 500/50 contains the active ingredients fluticasone propionate and salmeterol (as xinafoate).

Fluticasone propionate belongs to a group of medicines known as corticosteroids, frequently called 'steroids'. They are not 'anabolic steroids' which are the steroids sometimes misused by athletes.

Corticosteroids have an anti‐inflammatory action. They reduce the swelling and irritation in the walls of the small air passages in the lungs and so help you to breathe more easily. Corticosteroids are used to treat asthma and COPD.

Salmeterol (as xinafoate) is a bronchodilator. A bronchodilator keeps the breathing tubes in your lungs open and relieves the symptoms of asthma and other chest conditions. The effects of salmeterol (as xinafoate) last for up to twelve hours.

When taken together regularly fluticasone propionate and salmeterol help to control your breathing difficulties.

FLUTICASONE SALMETEROL CIPHALER 500/50 is used to help with asthma and chronic obstructive pulmonary disease (COPD) in people who need regular treatment.

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

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

DO NOT use this medicine to treat a sudden attack of breathlessness as it will not help you. You will need a different type of medicine, e.g. VENTOLIN (salbutamol), which you must not confuse with FLUTICASONE SALMETEROL CIPHALER 500/50.

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

Your doctor may have prescribed it for another reason.

This medicine is not addictive.

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

FLUTICASONE SALMETEROL CIPHALER 500/50 is available as a dry powder device known as an "inhaler".

  • FLUTICASONE SALMETEROL CIPHALER 500/50 (500 microgram fluticasone propionate and 50 microgram salmeterol)

2. What should I know before I use FLUTICASONE SALMETEROL CIPHALER 500/50?

Warnings

Do not use FLUTICASONE SALMETEROL CIPHALER 500/50 if:

  • you are allergic to fluticasone propionate or salmeterol (as xinafoate), lactose monohydrate or any of the ingredients listed at the end of this leaflet. Symptoms of an allergic reaction may include wheezing or difficulty breathing, swelling of the face, eyelids, lips/mouth, tongue or throat, chest pain or tightness, hay fever or lumpy rash or fainting.
  • always check the ingredients to make sure you can use this medicine.
  • the expiry date (EXP) printed on the pack has passed or if the packaging is torn and shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Check with your doctor if you:

  • have any allergies to any other medicines, foods, preservatives or dyes.
  • have any other medical conditions, including thrush in your mouth, tuberculosis, diabetes, a thyroid condition, high blood pressure or a heart problem, low blood potassium levels.
  • are taking other steroid medicines by mouth or inhalation.
  • take any medicines for any other condition.

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

Pregnancy and breastfeeding

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

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

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

FLUTICASONE SALMETEROL CIPHALER 500/50 contains lactose monohydrate

This medicine contains lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), talk to your doctor before taking this medicine.

3. What if I am taking other medicines?

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

Some medicines may interfere with FLUTICASONE SALMETEROL CIPHALER 500/50 and affect how it works.

These include:

  • Beta‐blockers used to treat high blood pressure (hypertension)
  • Ketoconazole used to treat fungal infection
  • Ritonavir used to treat HIV infection

These medicines may be affected by FLUTICASONE SALMETEROL CIPHALER 500/50 or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect FLUTICASONE SALMETEROL CIPHALER 500/50.

4. How do I use FLUTICASONE SALMETEROL CIPHALER 500/50?

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

They may differ from the information contained in this leaflet.

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

How much to take

It is very important that you use the medicine regularly every day. Do not stop treatment even if you feel better unless told to do so by your doctor.

Do not change your dose unless told to by your doctor.

If you are breathless or wheezing more often than normal, tell your doctor.

Asthma

Adults and adolescents 12 years and older:
Your doctor will prescribe a different strength of fluticasone propionate/salmeterol for you, depending on the severity of your condition. Lower strength fluticasone/salmeterol inhalers (100/50 & 250/50) may be available from other brands.

The usual dose is one puff from your FLUTICASONE SALMETEROL CIPHALER 500/50 twice a day.

Children below 12 years of age:
FLUTICASONE SALMETEROL CIPHALER 500/50 is not recommended in children below 12 years of age.

COPD

Adults:
Your doctor will prescribe 1 or 2 different strengths of fluticasone propionate/salmeterol for you – either 250/50 or 500/50.

The usual dose is one puff from your FLUTICASONE SALMETEROL CIPHALER 500/50 twice a day.

Follow the instructions provided and use FLUTICASONE SALMETEROL CIPHALER 500/50 until your doctor tells you to stop.

When to take FLUTICASONE SALMETEROL CIPHALER 500/50

Your doctor has chosen this medicine to suit you and your condition. FLUTICASONE SALMETEROL CIPHALER 500/50 is used to help with asthma and COPD in people who need regular treatment.

It is very important that you use your FLUTICASONE SALMETEROL CIPHALER 500/50 every day, twice a day. This will help you to keep free of symptoms throughout the day and night.

Take your medicine at about the same time(s) each day.

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

It does not matter if you take this medicine before or after food.

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

How to take FLUTICASONE SALMETEROL CIPHALER 500/50

The medicine in FLUTICASONE SALMETEROL CIPHALER 500/50 should be inhaled into your lungs.

FLUTICASONE SALMETEROL CIPHALER 500/50 must only be breathed in through the mouth.

Instructions for use

  • Your doctor, nurse or pharmacist should show you how to use your inhaler. They should check how you use it from time to time. Not using the FLUTICASONE SALMETEROL CIPHALER 500/50 properly or as prescribed may mean that it will not help your asthma as it should.
  • The inhaler device holds blisters containing salmeterol and fluticasone as a powder.
  • There is a counter on top of the inhaler which tells you how many doses are left. It counts down to 0. The numbers 5 to 0 will appear in red to warn you when there are only a few doses left. Once the counter shows 0, your inhaler is empty. See Figure A.

Using your inhaler

  1. To open your FLUTICASONE SALMETEROL CIPHALER 500/50, hold the outer case in one hand and put the thumb of your other hand on the thumbgrip. Push your thumb away from you as far as it will go. You will hear a click. This will open a small hole in the mouthpiece. See Figure B

  1. Hold your inhaler with the mouthpiece towards you. You can hold it in either your right or left hand. Slide the lever away from you as far as it will go. You will hear a click. This places a dose of your medicine in the mouthpiece. See Figure C.

Every time the lever is pulled back a blister is opened inside and the powder made ready for you to inhale. Do not play with the lever as this opens the blisters and wastes medicine.

  1. Hold the inhaler away from your mouth, breathe out as far as is comfortable. Do not breathe into your inhaler. See Figure D.

  1. Put the mouthpiece to your lips; breathe in steadily and deeply through the inhaler, not through your nose. See Figure E.
  • Remove the inhaler from your mouth.
  • Hold your breath for about 10 seconds or for as long as is comfortable.
  • Breathe out slowly.

  1. Afterwards, rinse your mouth with water and spit it out, and/or brush your teeth. This may help to stop you getting thrush and becoming hoarse. See Figure F.

  1. To close the inhaler, slide the thumbgrip back towards you, as far as it will go. You will hear a click. The lever will return to its original position and is reset. See Figure G.

Your inhaler is now ready for you to use again. As with all inhalers, caregivers should ensure that children prescribed FLUTICASONE SALMETEROL CIPHALER 500/50 use correct inhalation technique, as described above.

Cleaning your inhaler

Wipe the mouthpiece of the FLUTICASONE SALMETEROL CIPHALER 500/50 with a dry tissue to clean it.

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

Your FLUTICASONE SALMETEROL CIPHALER 500/50 inhaler is hygienically protected. It requires no maintenance and no refilling.

Use your medicine as your doctor has told you. If you are not sure ask your doctor or pharmacist.

After using FLUTICASONE SALMETEROL CIPHALER 500/50

Some people find that their mouth, throat or tongue becomes sore or that their voice becomes hoarse after inhaling this medicine. It may be helpful to rinse your mouth with water and spit it out after using your FLUTICASONE SALMETEROL CIPHALER 500/50. Tell your doctor but do not stop treatment unless told to do so.

If you forget to use FLUTICASONE SALMETEROL CIPHALER 500/50

FLUTICASONE SALMETEROL CIPHALER 500/50 should be used regularly at the same time each day If you miss your dose at the usual time, 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.

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

If you become wheezy or feel tight in the chest before the next dose is due, use a 'reliever puffer' in the usual way. You should get relief from your 'reliever puffer' within a few minutes.

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

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

If you use too much FLUTICASONE SALMETEROL CIPHALER 500/50

If you think that you have used too much FLUTICASONE SALMETEROL CIPHALER 500/50, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre (by calling 13 11 26 in Australia), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Symptoms of an overdose may include:

  • rapid heart beat
  • increased rate of breathing
  • significant muscle tremor
  • headache
  • increased blood pressure
  • increased blood sugar (glucose) levels

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

5. What should I know while using FLUTICASONE SALMETEROL CIPHALER 500/50?

Things you should do

  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking FLUTICASONE SALMETEROL CIPHALER 500/50.
  • 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.

It may affect other medicines used during surgery.

It is important that all doctors treating you are aware that you are on inhaled steroids. If your body is stressed by, for example, severe infection, surgical operation, an accident etc, you may need steroid tablets or injections for a time.

  • If you become pregnant while taking this medicine, or are trying to become pregnant, tell your doctor immediately. If you are about to have any blood tests, tell your doctor that you are taking this medicine.

It may interfere with the results of some tests.

  • Keep all of your doctor's appointments so that your progress can be checked. Tell your doctor if, for any reason, you have not used your medicine exactly as prescribed.

Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Call your doctor straight away if you:

  • Think you may be having an allergic reaction
  • Experience a change in your vision
  • Notice any symptoms listed in section 6

Things you should not do

  • Do not take FLUTICASONE SALMETEROL CIPHALER 500/50 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, or their symptoms seem similar to yours. Do not stop taking your medicine or change the dosage without checking with your doctor.

If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects. If possible, your doctor will gradually reduce the amount you take each day before stopping the medicine completely.

Driving or using machines

This medicine is not expected to affect your ability to drive a car or operate machinery. It is prudent to be careful driving or operating machinery until you know how FLUTICASONE SALMETEROL CIPHALER 500/50 affects you.

Looking after your medicine

  • Store below 25°C.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.
  • Keep it where children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

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

If your breathing or wheezing gets worse straight after using your inhaler, stop using it immediately and tell your doctor as soon as possible.

Less serious side effects

Less serious side effectsWhat to do
Mouth/throat:
  • hoarseness
  • soreness of mouth, throat or tongue
  • soreness in the oesophagus
Cardiovascular:
  • increased blood pressure
  • increase in heart rate
Pain:
  • headache
  • muscle cramps
  • pains in joints
Skin:
  • skin rash
  • bruises
Anxiety and behavioural changes:
  • sweating, trembling, feeling nervous or anxious
  • sleep disturbances
  • unusual activity and irritability (mainly in children)
Other:
  • slowing of growth in children and adolescents
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergic Reaction:
  • wheezing or difficulty breathing
  • swelling of the face, eyelids, lips/mouth, tongue or throat
  • chest pain or tightness
  • hay fever or lumpy rash ("hives")
  • fainting
Respiratory:
  • pneumonia (lung infection)
  • shortness of breath
Cardiovascular:
  • irregular heartbeat
Ocular:
  • eye problems (e.g. cataract, glaucoma)
Other:
  • rounded face
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Some side effects, for example changes in blood sugar (glucose) level, blood pressure or loss of bone density can only be found when your doctor does tests from time to time to check your progress.

Taking high doses of steroids for a long time could affect the adrenal glands, which make the body's own steroid. Your doctor may do tests to check how the adrenal glands are working.

Your doctor will be able to answer any questions you may have.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

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

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What FLUTICASONE SALMETEROL CIPHALER 500/50 contains

Active ingredient
(main ingredient)		fluticasone propionate salmeterol (as xinafoate)
Other ingredients
(inactive ingredients)		lactose monohydrate

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

What FLUTICASONE SALMETEROL CIPHALER 500/50 looks like

FLUTICASONE SALMETEROL CIPHALER 500/50 is a plastic inhaler device containing a foil strip of 60 blisters, containing medicine in a powder form.

Each blister contains 500 micrograms of the active ingredient fluticasone propionate.

Each blister also contains 50 micrograms of the active ingredient salmeterol.

Each blister also contains lactose monohydrate as a carrier.

The blisters protect the powder for inhalation from the effects of the atmosphere.

The FLUTICASONE SALMETEROL CIPHALER 500/50 inhaler device has a numeric dose counter which tells you the number of doses remaining. It counts down from 60 to 0. The numbers appear in red when the last five doses have been reached.

Never use your FLUTICASONE SALMETEROL CIPHALER 500/50 inhaler if the dose counter reads 0. When the counter shows 0 your FLUTICASONE SALMETEROL CIPHALER 500/50 inhaler is empty and should be disposed of.

Who distributes FLUTICASONE SALMETEROL CIPHALER 500/50

Cipla Australia Pty Ltd.,
Level 1, 132‐136 Albert Road,
South Melbourne, VIC 3205.
[email protected]
Toll Free number: 1800 569 074.

FLUTICASONE SALMETEROL CIPHALER 500/50

  • 500/50 ‐ AUST R 371362

This leaflet was prepared in September 2022.

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Fluticasone Salmeterol Ciphaler 500/50

Active ingredient

Fluticasone propionate; Salmeterol

Schedule

S4

 

1 Name of Medicine

Fluticasone propionate/salmeterol xinafoate.

2 Qualitative and Quantitative Composition

Each a foil strip contains regularly placed blisters each containing 500 micrograms of fluticasone propionate and 50 micrograms of salmeterol (as xinafoate).

Excipients with known effect.

Each blister of Fluticasone Salmeterol Ciphaler 500/50 contains 11.92 mg of lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Inhalation powder, pre-dispensed.
Fluticasone Salmeterol Ciphaler 500/50 is a white to off white powder filled in a strip of 60 blisters.

4 Clinical Particulars

4.1 Therapeutic Indications

For the regular treatment of asthma, where the use of a combination product is appropriate. This may include:
patients on effective maintenance doses of long-acting beta-2 agonists and inhaled corticosteroids;
patients who are symptomatic on current inhaled corticosteroid therapy.
For the symptomatic treatment of patients with severe COPD (FEV1 < 50% predicted normal) and a history of repeated exacerbations who have significant symptoms despite regular beta-2 agonist bronchodilator therapy. Fluticasone Salmeterol Ciphaler 500/50 is not indicated for the initiation of bronchodilator therapy in COPD.

4.2 Dose and Method of Administration

Fluticasone Salmeterol Ciphaler 500/50 must be used regularly for optimum benefit, even when asymptomatic.
Patients should be regularly assessed by a doctor, so the dose of Fluticasone Salmeterol Ciphaler 500/50 they are receiving remains optimal. Strength of dose should only be increased or decreased on medical advice.
The inhaler releases a powder that is inhaled into the lungs. The device is opened by sliding the lever. The mouthpiece is then placed in the mouth and the lips closed around it. The dose can then be inhaled and the device closed. A dose counter on the inhaler indicates the number of doses left.
For more detailed instructions for use refer to the patient information leaflet.

Asthma.

The dose of fluticasone propionate should be titrated to the lowest dose at which effective control of symptoms is maintained.
Patients should be given the dose of fluticasone propionate/salmeterol containing the appropriate fluticasone propionate dosage for the severity of their disease.

Adults and children over 12 years.

The recommended dose for regular asthma management is one inhalation (100 micrograms/50 micrograms to 500 micrograms/50 micrograms fluticasone propionate/salmeterol) twice daily.
(Patients requiring dose below 500 micrograms of fluticasone will need to be prescribed an alternative product.)
The recommended dose for initiation of maintenance therapy in moderate persistent asthma is one inhalation (100 micrograms/50 micrograms fluticasone propionate/salmeterol) twice daily.
Patients commenced on fluticasone propionate/salmeterol as initial maintenance therapy should be reviewed after 6-12 weeks. In patients whose asthma is well controlled and stable, cessation of salmeterol and transfer to maintenance therapy with an inhaled corticosteroid alone should be considered.

Children below 12 years of age.

Fluticasone Salmeterol Ciphaler 500/50 is not recommended in children below 12 years of age due to lack of data on safety and efficacy.

Special patient groups.

There is no need to adjust the dose in elderly patients or in those with renal or hepatic impairment.

COPD.

Adults.

The recommended dose is 250 micrograms/50 micrograms or 500 micrograms/50 micrograms fluticasone propionate/salmeterol twice daily:
Fluticasone propionate/salmeterol: One inhalation 500 micrograms/50 micrograms twice daily, or one inhalation 250 micrograms/50 micrograms twice daily may be a consideration in patients who are at a greater risk of inhaled corticosteroid adverse effects (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
(Patients requiring dose below 500 micrograms of fluticasone will need to be prescribed an alternative product.)

Method of administration.

Fluticasone Salmeterol Ciphaler 500/50 is for inhalation only.
Instructions for use. The patients should be shown how to use the inhaler. The inhaler should be checked from time to time. Not using the Fluticasone Salmeterol Ciphaler 500/50 properly or as prescribed may mean that it will not help the patient's asthma as it should.
The inhaler device holds blisters containing salmeterol and fluticasone as a powder.
The counter on top of the inhaler tells how many doses are left. It counts down to 0. The numbers 5 to 0 will appear in red to warn the patient when there are only a few doses left. Once the counter shows 0, the inhaler is empty.

Using inhaler.

1. To open Fluticasone Salmeterol Ciphaler 500/50, the outer case should be held in one hand and the thumb of other hand should be put on the thumb grip. The thumb should be pushed away as far as it will go. A click will be heard. This will open a small hole in the mouthpiece.
2. The inhaler should be held with the mouthpiece towards the patient. It can be held either on right or left hand. The lever should be slid away as far as it will go. A click will be heard. This places a dose of medicine in the mouthpiece.
Every time the lever is pulled back a blister is opened inside and the powder made ready to be inhaled. The lever should not be played with as this opens the blisters and wastes medicine.
3. The inhaler should be held away from the patient's mouth, and the patient should breathe out as far as is comfortable. The patient should not breathe into the inhaler.
4. The mouthpiece should be put to the patient's lips; the patient should breathe in steadily and deeply through the inhaler, not through nose.
The inhaler should be removed from the patient's mouth.
The patient's breath should be held for about 10 seconds or for as long as is comfortable.
The patient should breathe out slowly.
5. Afterwards, the patient should rinse their mouth with water and spit out, and/or brush their teeth. This may help from getting thrush and becoming hoarse.
6. To close the inhaler, the thumb grip should be slid back towards the patient, as far as it will go. A click will be heard. The lever will return to its original position and is reset.
The inhaler will be ready to use again.
As with all inhalers, it should be ensured that children prescribed Fluticasone Salmeterol Ciphaler 500/50 use correct inhalation technique, as described above.

Cleaning inhaler.

The mouthpiece of the Fluticasone Salmeterol Ciphaler 500/50 should be wiped with a dry tissue to clean it.

4.3 Contraindications

Fluticasone Salmeterol Ciphaler 500/50 is contraindicated in patients with a history of hypersensitivity to the active substances or to any of the excipients listed in Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

Use in asthma management plan.

The management of asthma should normally follow a stepwise program and patient response should be monitored clinically and by lung function tests. Treatment of asthma should be in accordance with current National asthma treatment guidelines.
Fluticasone propionate/salmeterol is not for relief of acute symptoms for which a fast- and short-acting inhaled bronchodilator (e.g. salbutamol) is required. Patients should be advised to have their relief medication available at all times.
Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician.
Sudden and progressive deterioration in control of asthma is potentially life threatening and the patient should be reviewed by a physician. Consideration should be given to increasing corticosteroid therapy. Also, where the current dosage of fluticasone propionate/salmeterol has failed to give adequate control of asthma, the patient should be reviewed by a physician. For patients with asthma or COPD, consideration should be given to additional corticosteroid therapies and administration of antibiotics if an exacerbation is associated with infection.
Treatment should not be stopped abruptly in patients with asthma due to risk of exacerbation; therapy should be titrated-down under physician supervision. For patients with COPD cessation of therapy may be associated with symptomatic decompensation and should be supervised by a physician.
There was an increased reporting of pneumonia in studies of patients with COPD receiving fluticasone propionate/salmeterol (see 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 pneumonia and exacerbation frequently overlap.
As with all medications containing corticosteroids, fluticasone propionate/salmeterol should be administered with caution in patients with active or quiescent pulmonary tuberculosis.
Fluticasone propionate/salmeterol should be administered with caution in patients with thyrotoxicosis.
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, fluticasone propionate/salmeterol should be used with caution in patients with pre-existing cardiovascular disease.
A transient decrease in serum potassium may occur with all sympathomimetic drugs at higher therapeutic doses. Therefore, fluticasone propionate/salmeterol should be used with caution in patients predisposed to low levels of serum potassium.
Rare instances of glaucoma and increased intraocular pressure have been reported following administration of inhaled corticosteroids. 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).
Care should be taken when transferring patients to fluticasone propionate/salmeterol therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy.
Fluticasone propionate/salmeterol should not be initiated in patients with unstable or acutely deteriorating asthma, which may be a life-threatening condition. Serious acute respiratory events, including fatalities, have been reported when salmeterol has been initiated in this situation. Although it is not possible from these reports to determine whether salmeterol contributed to these adverse events or failed to relieve the deteriorating asthma, the use of salmeterol in this setting is inappropriate.
Fluticasone propionate/salmeterol should not be used to transfer patients from oral to inhaled steroids.
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.
There have been very rare reports of increases in blood glucose levels (see Section 4.8 Adverse Effects (Undesirable Effects)) and this should be considered when prescribing to patients with a history of diabetes mellitus.
It was observed in a drug interaction study that concomitant use of systemic ketoconazole increases exposure to salmeterol. This may lead to prolongation in the QTc interval. Due to the potential increased risk of cardiovascular adverse events, the concomitant use of salmeterol with strong CYP3A4 inhibitors (e.g. ketoconazole, atazanavir, ritonavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir) is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties).
A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects.
As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator. Fluticasone propionate/salmeterol should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.
The pharmacological side-effects of beta-2 agonist treatment, such as tremor, subjective palpitations and headache, have been reported, but tend to be transient and may reduce with regular therapy.

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 (see Section 4.9 Overdose), reduction of bone mineral density, cataract, glaucoma and retardation of growth rate in children and adolescents.
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). However, adrenal function and adrenal reserve usually remain within normal range on inhaled fluticasone propionate therapy. To minimise the systemic effects of inhaled corticosteroids, including fluticasone propionate, each patient should be titrated down to the lowest dose that effectively controls his/her asthma (see Section 4.2 Dose and Method of Administration).
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 4.9 Overdose).

Use in the elderly.

There are no special precautions for use in the elderly.

Paediatric use.

Fluticasone Salmeterol Ciphaler 500/50 is not recommended as initiation of maintenance therapy in children. In children, less than 6 years of age, fluticasone propionate/salmeterol is recommended only after alternative options such as an ICS and/or leukotriene receptor antagonists (LTRA) have been trialled.
The growth of paediatric patients receiving corticosteroids, including fluticasone propionate, should be monitored. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained. To minimise the systemic effects of inhaled corticosteroids, including fluticasone propionate, each patient should be titrated down to the lowest dose that effectively controls his/her asthma (see Section 4.2 Dose and Method of Administration).
In children taking recommended doses of inhaled fluticasone propionate, adrenal function and adrenal reserve usually remain within the normal range. However, the possible effects of previous or intermittent treatment with oral steroids should not be discounted. Nevertheless, the benefits of inhaled fluticasone propionate should minimise the need for oral steroids.

Effects on laboratory tests.

No data available.

Lactose intolerance.

Fluticasone Salmeterol Ciphaler 500/50 also contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Both non-selective and selective beta-blockers should be avoided unless there are compelling reasons for their use.
Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after inhaled dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by fluticasone propionate are unlikely.
A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects.
Studies have shown that other inhibitors of cytochrome P450 3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in serum cortisol concentrations. Nevertheless, care is advised when co-administering potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole) as there is potential for increased systemic exposure to fluticasone propionate.
Co-administration of ketoconazole and salmeterol resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC). This increase in plasma salmeterol may cause a prolongation of QTc interval (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Neither fluticasone propionate nor salmeterol xinafoate alone show significant effects on fertility. Studies to detect such effects with co-administration have not been conducted.
(Category B3)
There are limited data from clinical trials in pregnant women. However, extensive clinical experience with drugs in this class has revealed no evidence of adverse effects on the mother or foetus at relevant therapeutic doses of ICS. As with any medication, administration during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.
An observational retrospective epidemiological cohort study utilising electronic health records from the United Kingdom was conducted to evaluate the risk of major congenital malformations (MCMs) following first trimester exposure to inhaled fluticasone propionate alone and salmeterol-fluticasone propionate relative to non-fluticasone propionate containing inhaled corticosteroids. No placebo comparator was included in this study.
Within the asthma cohort of 5362 first trimester inhaled corticosteroid-exposed pregnancies, 131 diagnosed MCMs were identified; 1612 (30%) were exposed to fluticasone propionate or salmeterol-fluticasone propionate of which 42 diagnosed MCMs were identified. The adjusted odds ratio for MCMs diagnosed by 1 year was 1.1 (95% CI: 0.5 - 2.3) for fluticasone propionate exposed vs non-fluticasone propionate inhaled corticosteroid exposed women with moderate asthma and 1.2 (95% CI: 0.7 - 2.0) for women with considerable to severe asthma. No difference in the risk of MCMs was identified following first trimester exposure to fluticasone propionate alone vs salmeterol-fluticasone propionate. Absolute risks of MCM across the asthma severity strata ranged from 2.0 to 2.9 per 100 fluticasone propionate-exposed pregnancies which is comparable to results from a study of 15,840 pregnancies unexposed to asthma therapies in the General Practice Research Database (2.8 MCM events per 100 pregnancies).
Results from the retrospective epidemiological study did not find an increased risk of MCMs following exposure to fluticasone propionate when compared to other inhaled corticosteroids, during the first trimester of pregnancy.
Reproductive toxicity studies in animals, either with single drug or in combination, revealed the foetal effects expected at excessive systemic exposure levels of a potent beta-2-adrenoceptor agonist and glucocorticosteroid - however these findings may not be relevant to humans taking inhaled steroids and beta-2 agonist at the recommended dose.
 Fluticasone propionate and salmeterol concentrations in plasma after inhaled doses are very low and therefore concentrations in human breast milk are likely to be correspondingly low. Studies in lactating animals support this for salmeterol xinafoate, although after subcutaneous administration of radiolabeled fluticasone propionate to lactating rats, levels of radioactivity in milk were 3 to 7 times plasma levels. There are no data available for human breast milk.
Administration during lactation should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

4.7 Effects on Ability to Drive and Use Machines

Fluticasone propionate/salmeterol is unlikely to produce an effect.

4.8 Adverse Effects (Undesirable Effects)

As Fluticasone Salmeterol Ciphaler 500/50 contains fluticasone propionate and salmeterol the type and severity of adverse reactions associated with each of the compounds may be expected. There is no evidence of additional adverse events following concurrent administration of the two compounds.
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000) and very rare (< 1/10,000).

Clinical trial data.

Infections and infestations.

Common: Candidiasis of mouth and throat, pneumonia (in COPD patients).
Such patients may find it helpful to rinse out their mouth with water after inhalation.
Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the fluticasone propionate.
Rare: Oesophageal candidiasis.

Immune system disorders.

Hypersensitivity reactions. Uncommon: Cutaneous hypersensitivity reactions, dyspnoea.
Rare: Anaphylactic reactions.

Endocrine disorders.

Possible systemic effects include (see Section 4.4 Special Warnings and Precautions for Use):
Uncommon: Cataract.
Rare: Glaucoma.

Metabolism and nutrition disorders.

Uncommon: Hyperglycaemia.

Psychiatric disorders.

Uncommon: Anxiety, sleep disorders.
Rare: Behavioural changes, including hyperactivity and irritability (predominantly in children).

Nervous system disorders.

Very common: Headache (see Section 4.4 Special Warnings and Precautions for Use).
Uncommon: Tremor (see Section 4.4 Special Warnings and Precautions for Use).

Cardiac disorders.

Common: Palpitations (see Section 4.4 Special Warnings and Precautions for Use).
Uncommon: Tachycardia, atrial fibrillation.
Rare: Cardiac arrhythmias including supraventricular tachycardia and extrasystoles.
Peripheral vasodilation and a compensatory small increase in heart rate may occur in some patients.

Respiratory, thoracic and mediastinal disorders.

Common: Hoarseness/dysphonia, throat irritation.

Skin and subcutaneous tissue disorders.

Uncommon: Contusions.

Musculoskeletal and connective tissue disorders.

Common: Muscle cramps, arthralgia.

Post-marketing data.

Immune system disorders.

Hypersensitivity reactions manifesting as:
Uncommon: Cutaneous hypersensitivity reactions.
Rare: Angioedema (mainly facial and oropharyngeal oedema) and respiratory symptoms (dyspnoea and/or bronchospasm), anaphylactic reactions.

Endocrine disorders.

Possible systemic effects include (see Section 4.4 Special Warnings and Precautions for Use):
Rare: Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density.

Metabolism and nutrition disorders.

Uncommon: Hyperglycaemia.

Psychiatric disorders.

Uncommon: Anxiety, sleep disorders.
Rare: Behavioural changes, including hyperactivity and irritability (predominantly in children).

Respiratory, thoracic and mediastinal disorders.

Rare: Paradoxical bronchospasm (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

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

4.9 Overdose

The available information on overdose with fluticasone propionate/salmeterol, fluticasone and/or salmeterol is given below:
It is not recommended that patients receive higher than approved doses of fluticasone propionate/salmeterol. It is important to review therapy regularly and titrate down to the lowest dose at which effective control of disease is maintained (see Section 4.2 Dose and Method of Administration).

Symptoms and signs.

The expected symptoms and signs of salmeterol overdosage are those typical of excessive beta-2-adrenergic stimulation, including tremor, headache, tachycardia, increases in systolic blood pressure, hypokalaemia and raised blood glucose levels.
Acute inhalation of fluticasone propionate doses in excess of those approved may lead to temporary suppression of the hypothalamic-pituitary-adrenal axis. This does not usually require emergency action as normal adrenal function typically recovers within a few days.
If higher than approved doses of fluticasone propionate/salmeterol are continued over prolonged periods, significant adrenocortical suppression is possible. There have been very rare reports of acute adrenal crisis, mainly occurring in children exposed to higher than approved doses over prolonged periods (several months or years). Presenting symptoms are typically vague and may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, decreased levels of consciousness, hypoglycaemia and seizures. Situations which could potentially trigger acute adrenal crisis include exposure to trauma, surgery, infection or any rapid reduction in the dosage of the inhaled fluticasone propionate component. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Treatment.

There is no specific treatment for an overdose of salmeterol and fluticasone propionate. If overdose occurs, the patient should be treated supportively with appropriate monitoring necessary.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fluticasone Salmeterol Ciphaler 500/50 contains fluticasone propionate and salmeterol xinafoate which have differing modes of action. Salmeterol provides symptomatic relief, while fluticasone propionate improves lung function and prevents exacerbations of the condition. Fluticasone propionate/salmeterol can offer a more convenient regimen for patients on concurrent long-acting beta-agonist and inhaled corticosteroid therapy. The respective mechanisms of action of both drugs are discussed below.

Fluticasone propionate.

Fluticasone propionate given by inhalation at recommended doses has potent glucocorticoid activity in the airway. The potent anti-inflammatory action improves the symptomatic control of asthma, allows reduction of other drugs, such as rescue bronchodilators, and may limit the risk of decline in lung function over time. The low systemic bioavailability of fluticasone propionate provides a better risk: benefit outcome without the adverse effects that accompany systemically administered corticosteroids.

Salmeterol.

Salmeterol is a selective long-acting beta-2-adrenoceptor agonist and at dosages of less than 100 microgram twice daily has little measurable cardiovascular effect. Salmeterol xinafoate is a racemate, the R-enantiomer being active.
The pharmacological properties of salmeterol offer a slower onset of action, but more effective protection against histamine-induced bronchoconstriction and a longer duration of bronchodilation (lasting for approximately 12 hours) than recommended doses of conventional short-acting beta-2 agonists. The onset of effective bronchodilation (> 15% improvement in FEV1) occurs within 10 to 30 minutes and peak effect occurs between 3 to 4 hours.
In vitro tests have shown salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes and prostaglandin D2, from human lung fragments. In one study in man, salmeterol inhibits the early and late phase response to inhaled allergen; the latter persisting for over 30 hours after a single dose when the bronchodilator effect is no longer evident.
Single dosing with salmeterol attenuates bronchial hyperresponsiveness. These properties indicate that salmeterol has additional non-bronchodilator activity, but the full clinical significance is not yet clear. The mechanism is different from the anti-inflammatory effect of corticosteroids.

Clinical trials.

Asthma. Clinical trials have investigated the safety and efficacy data of fluticasone propionate/salmeterol at three dose strengths (100 micrograms/50 micrograms, 250 micrograms/50 micrograms and 500 micrograms/50 micrograms) in the treatment of patients with reversible obstructive airways disease and asthma. Six studies of 12 or 28 week duration have been carried out in a total of 2080 patients (1671 adults, 152 adolescents and 257 children), of which 769 were treated with fluticasone propionate/salmeterol.
Three studies used the 100 micrograms/50 micrograms dose strength (338 patients), two the 250 micrograms/50 micrograms dose strength (264 patients) and one the 500 micrograms/50 micrograms dose strength (167 patients). All studies were of double blind, randomised, parallel group design, and aimed to demonstrate superiority of the combination product over its constituent drugs at each dose strength, or equivalence of the combination product compared to the two drugs taken concurrently from separate inhalers (concurrent therapy).

Fluticasone propionate/salmeterol vs. salmeterol alone or fluticasone propionate alone.

In two studies using the 100 micrograms/50 micrograms and 250 micrograms/50 micrograms doses, the primary efficacy variables were probability of remaining in the study, mean change from baseline in morning pre-dose FEV1 at endpoint and mean serial FEV1 AUC at Week 1. Patients were symptomatic and demonstrated room for improvement in lung function. Fluticasone propionate/salmeterol was significantly more effective (p < 0.001) than placebo or salmeterol alone in all primary efficacy comparisons. In addition, fluticasone propionate/salmeterol was significantly more effective than fluticasone propionate alone in all primary efficacy comparisons (p ≤ 0.007) except for probability of remaining in the study for the 100 micrograms/50 micrograms dose (p=0.084).
Effects of fluticasone propionate/salmeterol were maintained over the treatment period. FEV1 results measured over 12 hours after 1 week of treatment or after 12 weeks of treatment were similar but higher than those seen after the first dose of fluticasone propionate/salmeterol. Fluticasone propionate/salmeterol produced clinically significant improvements in quality of life (> 0.5 as assessed by the Asthma Quality of Life Questionnaire) in both studies.
In a third study, fluticasone propionate/salmeterol 500 micrograms/50 micrograms was significantly more effective than fluticasone propionate alone (p < 0.001). Higher mean changes in morning PEF were seen in the fluticasone propionate/salmeterol group for Weeks 1-12 (95% confidence intervals for the treatment difference were -29 L/min to -12 L/min). As well as the marked improvements in lung function seen with fluticasone propionate/salmeterol, reductions in rescue salbutamol use and an increase in the percentage of symptom-free days were seen. Significant differences compared with placebo and with salmeterol alone or fluticasone propionate alone were seen in most of these parameters. Improvements were noted over the first week of dosing.

Fluticasone propionate/salmeterol vs. concurrent therapy.

Four double-blind, double-dummy studies assessed clinical equivalence of fluticasone propionate/salmeterol with concurrent therapy with salmeterol and fluticasone propionate. Three were conducted in symptomatic adults and adolescents and one in paediatric patients.
In all studies, large increases in mean morning PEF were seen over Weeks 1-12 in both treatment groups. Improvements were already apparent over Week 1.
Results for the primary efficacy variable (mean morning PEF over Weeks 1-12 in the Intent-to-Treat Population) met the criterion for clinical equivalence (90% confidence limits for the difference between treatments contained within ± 15 L/min) in three of the four studies. In one study, the data suggested fluticasone propionate/salmeterol had slightly greater efficacy compared to concurrent administration of salmeterol and fluticasone propionate (difference -9 L/min; 90% confidence limits - 17, 0 L/min; 95% confidence limits - 19, 2 L/min).
Both fluticasone propionate/salmeterol and concurrent therapy improved symptom scores, decreased rescue salbutamol usage and increased the percentage of symptom free days and nights. Effects of the two treatments appeared to be similar on these parameters with statistical comparisons generally showing no clinically relevant differences between treatments.
Clinic measures of FEV1 were made at each clinic visit. Improvements seen at 2 weeks were similar to those seen after 12 weeks treatment. In a 28-week study, efficacy, as measured by FEV1, was maintained throughout the duration of treatment. Results were not dependent on the type of pre-study corticosteroid used.

Safety and efficacy of fluticasone propionate/salmeterol vs fluticasone propionate alone in asthma.

Two multi-centre 26-week studies were conducted to compare the safety and efficacy of fluticasone propionate/salmeterol vs fluticasone propionate alone, one in adult and adolescent subjects (AUSTRI trial), and the other in paediatric subjects 4-11 years of age (VESTRI trial). Both studies enrolled subjects with a history of asthma-related hospitalisation or asthma exacerbation in the previous year. 17% and 33% of enrolled subjects in AUSTRI and VESTRI, respectively, had persistent asthma with a history of at least 2 asthma-related hospitalisations or asthma exacerbations in the previous year. The primary objective of each study was to determine whether the addition of LABA to ICS therapy (fluticasone propionate/salmeterol) was non-inferior to ICS (fluticasone propionate) alone in terms of the risk of serious asthma related events (asthma-related hospitalisation, endotracheal intubation, and death). A secondary efficacy objective of these studies was to evaluate whether ICS/LABA (fluticasone propionate/salmeterol) was superior to ICS therapy alone (fluticasone propionate) in terms of severe asthma exacerbation (defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an in-patient hospitalisation or emergency department visit due to asthma that required systemic corticosteroids).
A total of 11,679 and 6,208 subjects were randomised and received treatment in the AUSTRI and VESTRI trials, respectively. For the primary safety endpoint, non-inferiority was achieved for both trials (see Table 1).
For the secondary efficacy endpoint, reduction in time to first asthma exacerbation for fluticasone propionate/salmeterol relative to fluticasone propionate was seen in both studies, however only AUSTRI met statistical significance. See Table 2.

Salmeterol multi-center asthma research trial (SMART).

The Salmeterol Multi-center Asthma Research Trial (SMART) was a 28-week US study that evaluated the safety of salmeterol compared to placebo added to usual therapy in adult and adolescent subjects. Although there were no significant differences in the primary endpoint of the combined number of respiratory-related deaths and respiratory-related life-threatening experiences, the study showed a significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated with salmeterol vs 3 deaths out of 13,179 patients on placebo). The study was not designed to assess the impact of concurrent inhaled corticosteroid use.
To evaluate the safety profile of salmeterol, a meta-analysis of 215 studies comprising 106,575 patients with over 39,000 patient-years exposure was performed. The meta-analysis evaluated asthma-related hospitalisations, asthma-related deaths, asthma-related intubations and all-cause death when salmeterol was used alone and when salmeterol was used with an ICS. There was no evidence of increased risk for asthma-related hospitalisations or asthma-related deaths in patients using salmeterol with an ICS as a fixed dose combination product.
Initial maintenance therapy - moderate persistent asthma. Moderate persistent asthma is characterised by daily symptoms over a prolonged period of time or nocturnal asthma more than once a week, a peak expiratory flow rate (PEFR) or FEV1 of 60-80% of predicted and a variability in PEFR or FEV1 of > 30%.

Fluticasone propionate/salmeterol 100 micrograms/50 micrograms vs fluticasone propionate (FP) 100 micrograms bd.

The data of four randomised, double blind, controlled, parallel group studies, SAS30001 (n=168), SAS30003 (n=86), SAS30017 (n=150) and SAM40027 Stratum 1 Addendum (n=404) were integrated to examine the safety and efficacy of fluticasone propionate/salmeterol 100 micrograms/50 micrograms bd as initial maintenance therapy over a 12 week treatment period in subjects aged ≥ 12 years with moderate persistent asthma. The results showed that the mean improvement from baseline in morning pre-dose PEF over Weeks 1-12 and Endpoint (primary endpoint - defined as the mean of the last available 7 days of on-treatment data for each subject) were significantly higher with fluticasone propionate/salmeterol 100 micrograms/50 micrograms bd than with FP 100 micrograms bd (treatment difference vs FP: 23.8 L/min and 24.0 L/min respectively, p < 0.001).
Fluticasone propionate/salmeterol was also superior for the secondary endpoints, including pre-dose FEV1; serial FEV1; % of days with no asthma symptoms; % of nights with no awakenings; and % of rescue free days. Additionally, a higher proportion of patients achieved 'Well controlled' asthma over Weeks 5-12 with fluticasone propionate/salmeterol 100 micrograms/50 micrograms bd vs FP 100 micrograms bd (46% vs 29%, respectively, odds ratio 2.04 in favour of fluticasone propionate/salmeterol, p < 0.001).
This integrated analysis demonstrated both statistical and clinical superiority of fluticasone propionate/salmeterol 100 micrograms/50 micrograms bd compared with FP 100 micrograms bd in improving lung function, reducing symptoms and attaining asthma control.
Furthermore, one of the keys studies, SAM40027 Stratum 1 Addendum, demonstrated that initial maintenance therapy with fluticasone propionate/salmeterol brought about significantly more rapid asthma control compared with FP alone. Specifically, this study showed that in the first twelve weeks of treatment, the time taken for 50% of subjects to achieve the first week of 'Well-controlled' asthma was 16 days for fluticasone propionate/salmeterol 100 micrograms/50 micrograms bd, compared to 30 days with FP 100 micrograms bd alone (p=0.003).
Subgroup analyses: Additional subgroup analyses were undertaken of all fluticasone propionate/salmeterol 100 micrograms/50 micrograms bd studies in the target population to explore/further define patients who were likely to benefit most from treatment with fluticasone propionate/salmeterol as initial maintenance therapy. The greatest incremental benefit in the percentage of subjects with 'well-controlled' asthma on fluticasone propionate/salmeterol vs FP alone was demonstrated in subjects exhibiting all three clinical features: daily symptoms, daily use of rescue medication, moderate/severe airflow limitation (i.e. FEV1 ≤ 80%). In this population, 43% of subjects on fluticasone propionate/salmeterol achieved 'well controlled' asthma as compared with 23% on FP alone over the first 12 weeks of treatment. This represents a 2.6-fold difference (95% confidence interval: 1.87, 3.62) in favour of fluticasone propionate/salmeterol, and is a greater margin of difference than previously demonstrated in the overall data (integrated data: odds ratio 2.04).
In patients with all three stated baseline features, significant treatment differences were seen between fluticasone propionate/salmeterol and FP alone for PEF, symptoms and rescue use. Improvement in PEF was 26 L/min greater with fluticasone propionate/salmeterol than with FP alone (95% CI 19.3, 32.6) and patients treated with fluticasone propionate/salmeterol were twice as likely to be symptom-free than patients treated with FP alone over the first 12 weeks of treatment (odds ratio fluticasone propionate/salmeterol /FP 2.05, 95% CI 1.54, 2.74, p < 0.001). Likewise, the fluticasone propionate/salmeterol group had significantly more rescue-free days compared with FP alone (p < 0.001).
Additionally, in this group of patients the time to first achieving 'well controlled' asthma was significantly shorter with fluticasone propionate/salmeterol compared with FP alone (median time to first week of 'well controlled' asthma was 9 days for fluticasone propionate/salmeterol and 16 days for FP, p < 0.001).

Dosage adjustment with fluticasone propionate/salmeterol vs fluticasone propionate (FP).

Two studies, SAS30040 (n=484) and SAM40027 Stratum 1 Addendum (n=404) demonstrated fluticasone propionate/salmeterol to be a superior option to FP alone in two situations, (i) dosing step-down once control has been achieved with fluticasone propionate/salmeterol and (ii) dosing step-up where the patient failed to achieve control with the initial doses of medication.
For patients who have achieved control with a maintenance dose of fluticasone propionate/salmeterol 250 micrograms/50 micrograms bd, SAS30040 demonstrated that stepping down the dose to fluticasone propionate/salmeterol 100 micrograms/50 micrograms bd is more effective than removing the LABA component, and switching patients to FP 250 micrograms bd. This study showed PEF values to be maintained over 12 weeks after stepping down to fluticasone propionate/salmeterol 100 micrograms/50 micrograms, but a decline in PEF values was noted with FP 250 micrograms during the same period (treatment difference of 12.9 L/min in favour of fluticasone propionate/salmeterol, p < 0.001).
For patients in whom control was not achieved with an initial dose of fluticasone propionate/salmeterol or FP as initial maintenance therapy, SAM40027 Stratum 1 Addendum demonstrated the benefits of dosing step-up with fluticasone propionate/salmeterol compared with FP alone. The study confirmed that subjects in the fluticasone propionate/salmeterol group had 1.67 greater chance of achieving 'Well-controlled' asthma at the same or lower ICS doses compared to FP alone (odds ratio 1.67, p=0.006). The fact that more patients were achieving control at the earlier treatment steps with fluticasone propionate/salmeterol indicated that, overall, control was achieved earlier in the study with fluticasone propionate/salmeterol than with FP alone, highlighting the time superiority of the combination.
Chronic obstructive pulmonary disease (COPD). Three randomised, double blind, placebo-controlled trials have investigated the safety and efficacy of fluticasone propionate/salmeterol dry powder inhaler in the treatment of patients with COPD. The studies used two fluticasone propionate/salmeterol dose strengths (250 micrograms/50 micrograms and 500 micrograms/50 micrograms). All studies comprised four treatment arms: fluticasone propionate/salmeterol, salmeterol, fluticasone propionate, placebo. Salmeterol is currently registered for the treatment of COPD.
Fluticasone propionate/salmeterol vs salmeterol alone: The primary efficacy variable for the three studies was mean change in morning pre-dose FEV1. In the ITT analysis, a statistically significant difference in the primary endpoint in favour of fluticasone propionate/salmeterol was seen across all three studies. For multiple measured secondary endpoints, fluticasone propionate/salmeterol 500 micrograms/50 micrograms was superior by a clinically significant degree only for dyspnoea vs salmeterol alone. In addition, fluticasone propionate/salmeterol 250 micrograms/50 micrograms was statistically significantly superior to salmeterol for % days without use of reliever medication and % of nights without awakening.
Post-hoc subgroup analyses were performed for those patients with severe COPD (FEV1 < 50% predicted normal). There were 1724 patients in the severe subgroup, of whom 415 received fluticasone propionate/salmeterol. A statistically significant treatment difference in favour of fluticasone propionate/salmeterol (both doses) was seen in the primary endpoint in two of the three studies. The clinical significance of these results is uncertain. For multiple measured secondary endpoints, fluticasone propionate/salmeterol 500 micrograms/50 micrograms produced a clinically significant improvement in breathlessness and a clinically significant reduction in % of days without use of reliever medication (1 time per day) compared with salmeterol alone.

5.2 Pharmacokinetic Properties

There is no evidence in animal or human subjects that the administration of fluticasone propionate and salmeterol together by the inhaled route affects the pharmacokinetics of either component. For pharmacokinetic purposes therefore each component can be considered separately.
Even though plasma levels of fluticasone propionate/salmeterol are very low, potential interactions with other substrates and inhibitors of CYP 3A4 cannot be excluded.

Fluticasone propionate.

Following oral administration 87-100% of the dose is excreted in the faeces, up to 75% as parent compound depending on the dose. There is a non-active major metabolite. Following intravenous administration there is rapid plasma clearance suggestive of extensive hepatic extraction. The plasma elimination half-life is approximately 3 hours. The volume of distribution is approximately 250 litres. Doses delivered by the dry powder inhalers and metered-dose inhalers may not have the same systemic bioavailability; however, there is no difference in clinical efficacy between the inhalers in controlled studies.
The absolute bioavailability of fluticasone propionate for each of the available inhaler devices has been estimated from within and between study comparisons of inhaled and intravenous pharmacokinetic data based on AUC(0-infinity) data. In healthy adult subjects the absolute bioavailability has been estimated for fluticasone propionate dry powder inhaler (8%), fluticasone propionate Diskhaler (9%) and fluticasone propionate Inhaler (10.9%) respectively. The absolute bioavailability from fluticasone propionate/salmeterol dry powder inhaler and inhaler are approximately 6%.

Salmeterol.

Salmeterol acts locally in the lung, therefore plasma levels are not predictive of therapeutic effect. In addition, there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying very low plasma concentrations (approximately 200 picograms/mL or less) of the drug after inhaled dosing.
Following administration, salmeterol xinafoate is extensively bound (95-98%) to plasma proteins. Elimination of radioactivity from plasma following oral administration of radiolabelled salmeterol xinafoate is slow (mean t1/2 is 67 hours). Excretion is predominantly through the faeces and to a lesser extent urine. Aliphatic hydroxylation appears to be the major route of metabolism in humans.
After regular dosing with salmeterol xinafoate, the xinafoate moiety, hydroxynaphthoic acid, can be detected in the systemic circulation, reaching steady state concentrations of approximately 100 nanograms/mL. These concentrations are up to 1000-fold lower than steady state levels observed in toxicity studies and in longer-term regular dosing (more than 12 months) trials in patients with airways obstruction, there have not been adverse effects attributable to hydroxynaphthoic acid reported.
In a placebo-controlled, crossover drug interaction study in 20 healthy subjects, coadministration of salmeterol (50 micrograms twice daily inhaled) and the CYP3A4 inhibitor ketoconazole (400 mg once daily orally) for 7 days resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC). There was no increase in salmeterol accumulation with repeat dosing. Three subjects were withdrawn from salmeterol and ketoconazole co-administration due to QTc prolongation or palpitations with sinus tachycardia. The increase in the QTc interval observed with the co-administration of salmeterol and ketoconazole compared with salmeterol and placebo administration was not statistically significant. There were no clinically significant effects seen in heart rate or blood potassium levels, which were the primary endpoints of the study (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

5.3 Preclinical Safety Data

Fluticasone propionate and salmeterol xinafoate have been extensively evaluated in animal toxicity tests. Significant toxicities occurred only at doses in excess of those recommended for human use and were those expected for a potent beta-2-adrenoreceptor agonist and glucocorticosteroid.
Co-administration of fluticasone propionate and salmeterol resulted in some cardiovascular lesions not seen upon dosing with the individual drugs (mild atrial myocarditis and focal coronary arteritis in rats and papillary muscle necrosis in dogs). However, these high dose changes were not consistently observed across studies and are unlikely to be of clinical relevance.
Co-administration did not modify other class-related toxicities in animals.

Genotoxicity.

Neither fluticasone propionate nor salmeterol xinafoate showed evidence of mutagenic potential when tested alone in a standard battery of genotoxicity assays. No studies examining the potential interaction of fluticasone propionate and salmeterol xinafoate to cause genetic toxicity when co-administered have been conducted.
The non-CFC propellant, norflurane (HFA134a), has been shown to have no toxic effect at very high vapour concentrations, far in excess of those likely to be experienced by patients, in a wide range of animal species exposed daily for periods of two years.

Carcinogenicity.

No studies on the carcinogenic potential of the combined formulation of fluticasone propionate/salmeterol xinafoate have been conducted in animals. With fluticasone alone, no evidence of a tumorigenic effect was observed in either a 2 year study in rats receiving doses of fluticasone propionate up to 57 mg/kg/day by inhalation or in an 18 month study in mice receiving oral doses of fluticasone propionate up to 1 mg/kg/day. With salmeterol xinafoate alone, oral administration to mice at 0.2, 1.4 or 10 mg/kg/day for 18 months resulted in the development of smooth muscle tumours (lieomyomas and possibly liemyosarcomas) in the uterus. In rats, combined oral / inhalational administration for 24 months at total dose levels of 0.2, 0.7 and 2.6 mg/kg/day resulted in leiomyomas in the suspensory ligament of the ovaries, as well as an increased incidence of benign pituitary tumours. The smooth muscle tumours in both species are thought to result from chronic stimulation of beta-adrenoceptors in these tissues, whereas the mechanism involved in the development of the pituitary tumours is unknown.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate.

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.

6.4 Special Precautions for Storage

Do not store above 25°C.

6.5 Nature and Contents of Container

Plastic inhaler containing a foil blister strip with 60 blisters each containing powder formulation of 500 micrograms of fluticasone propionate and 50 micrograms of salmeterol (as xinafoate).
The inhaler is packaged in a plastic-coated, moisture-protective pack.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Fluticasone Salmeterol Ciphaler 500/50 contain the active ingredients fluticasone propionate and salmeterol (as xinafoate).

Fluticasone propionate.

Chemical name: The chemical name of fluticasone propionate is S-fluoromethyl 6α, 9α-difluoro-11ß-hydroxy-16α-methyl-3-oxo-17 α-propionyloxy-androsta-1, 4-diene-17ß-carbothioate.
Molecular formula: C25H31F3O5S.
Molecular weight: 500.6.

Chemical structure.


Description: Fluticasone propionate is a white to almost white powder. It is sparingly soluble in methylene chloride, slightly soluble in alcohol, and practically insoluble in water.

CAS number.

80474-14-2.

Salmeterol (as xinafoate).

Chemical name: The chemical name of salmeterol xinafoate is (±)-4-Hydroxy-α1-[[[6-(4-phenylbutoxy) hexyl]amino]methyl]-m-xylene-α,α'-diol 1-hydroxy-2-naphthoate (salt).
Molecular formula: C25H37NO4.C11H8O3.
Molecular weight: 603.8.

Chemical structure.


Description: Salmeterol xinafoate is a white to almost white powder. It is soluble in methanol, slightly soluble in anhydrous ethanol, and practically insoluble in water.

CAS number.

94749-08-3.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

Summary Table of Changes