Consumer medicine information

Salflumix Easyhaler

Fluticasone propionate; Salmeterol

BRAND INFORMATION

Brand name

Salflumix Easyhaler

Active ingredient

Fluticasone propionate; Salmeterol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Salflumix Easyhaler.

SUMMARY CMI

SALFLUMIX EASYHALER®

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 SALFLUMIX EASYHALER?

SALFLUMIX EASYHALER contains the active ingredients fluticasone propionate and salmeterol. SALFLUMIX EASYHALER is used to help prevent breathing problems such as Asthma and Chronic Obstructive Pulmonary Disease (COPD).

DO NOT use this medicine to treat a sudden attack of breathlessness as it will not help you. If that happens you need to use a fast acting ‘reliever’ medication.

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

2. What should I know before I use SALFLUMIX EASYHALER?

Do not use if you have ever had an allergic reaction to SALFLUMIX EASYHALER 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 SALFLUMIX EASYHALER? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with SALFLUMIX EASYHALER 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 SALFLUMIX EASYHALER?

  • SALFLUMIX EASYHALER should be used twice daily.
  • Use SALFLUMIX EASYHALER every day as directed by your doctor. This will make sure that it works properly in controlling your asthma or COPD.

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

5. What should I know while using SALFLUMIX EASYHALER?

Things you should do
  • Remind any doctor, dentist, surgeon, anaesthetist or pharmacist you visit that you are using SALFLUMIX EASYHALER.
  • Rinse your mouth after using SALFLUMIX EASYHALER
Things you should not do
  • Do not stop using this medicine suddenly.
Driving or using machines
  • SALFLUMIX EASYHALER is unlikely to affect your ability to drive or use machinery but you should be careful until you know how SALFLUMIX EASYHALER affects you.
Looking after your medicine
  • Store SALFLUMIX EASYHALER below 25°C and protect from moisture.
  • Keep the inhaler in the foil bag until you are ready to start using it.
  • Place the inhaler in the protective cover provided after you take it out of the foil bag.

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

6. Are there any side effects?

Common side effects include sore, yellowish, raised patches in the mouth (thrush); shakiness; headache and rapid heartbeat.

Tell your doctor if you notice you feel more wheezy, your chest may feel tight more often or you have increased coughing or breathing problems.

Some side effects can only be found when your doctor does tests from time to time to check your progress.

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

SALFLUMIX EASYHALER®

Active ingredients: Fluticasone propionate and Salmeterol

Consumer Medicine Information (CMI)

This leaflet provides important information about using SALFLUMIX EASYHALER. 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 SALFLUMIX EASYHALER.

Where to find information in this leaflet:

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

1. Why am I using SALFLUMIX EASYHALER?

SALFLUMIX EASYHALER contains two active ingredients, fluticasone propionate and salmeterol.

  • Fluticasone propionate is a corticosteroid which reduces swelling and irritation in the lungs.
  • Salmeterol is a long-acting bronchodilator.
    Bronchodilators help the airways in the lungs to stay open. This makes it easier for air to get in and out. The effects last for up to 12 hours.

SALFLUMIX EASYHALER is used to help prevent breathing problems such as:

  • Asthma
  • Chronic Obstructive Pulmonary Disease (COPD)

SALFLUMIX EASYHALER helps to prevent breathlessness and wheeziness in people who need regular treatment.

DO NOT use this medicine to treat a sudden attack of breathlessness as it will not help you. If that happens you need to use a fast acting ‘reliever’ medication, such as salbutamol.

2. What should I know before I use SALFLUMIX EASYHALER?

Warnings

Do not use SALFLUMIX EASYHALER if:

  • you are allergic to fluticasone propionate, salmeterol xinafoate, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

If you have breathing difficulties or wheezing that get worse straight after using SALFLUMIX EASYHALER stop using your SALFLUMIX EASYHALER inhaler. Use your fast-acting ‘reliever’ inhaler to help your breathing and tell your doctor straight away.

Check with your doctor if you:

  • have or have had any other medical conditions especially the following:
    - thrush in your mouth
    - tuberculosis
    - diabetes
    - a thyroid condition
    - high blood pressure
    - heart problems including an irregular or fast heartbeat
    - low blood potassium levels
  • 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.

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 SALFLUMIX EASYHALER and affect how it works.

Tell your doctor about any other medicines you are taking especially the following:

  • Beta-blockers (such as atenolol, metoprolol, propranolol) used to treat high blood pressure and other heart conditions
  • Ketoconazole, a medicine used to treat fungal infections
  • Ritonavir, a medicine used to treat HIV infection.
  • Any other steroid medicines (taken by mouth or as an injection) used to treat swelling, inflammation or breathing problems.

These medicines may be affected by SALFLUMIX EASYHALER 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 SALFLUMIX EASYHALER.

4. How do I use SALFLUMIX EASYHALER?

How much to use

Use SALFLUMIX EASYHALER every day, until your doctor advises you to stop

Follow the instructions provided and use SALFLUMIX EASYHALER until your doctor tells you to stop. Do not exceed the recommended dose. Check with your doctor or pharmacist if you are not sure.

For Asthma

Adults and children over 12 years

  • One inhalation of SALFLUMIX EASYHALER 250/50 or SALFLUMIX EASYHALER 500/50 twice daily.

For Chronic Obstructive Pulmonary Disease (COPD)

Adults

  • One inhalation of SALFLUMIX EASYHALER 250/50 or SALFLUMIX EASYHALER 500/50 twice daily.

Easyhaler is not recommended for use in children below 12 years of age.

When to use SALFLUMIX EASYHALER

  • SALFLUMIX EASYHALER should be used twice daily.
  • You must use SALFLUMIX EASYHALER every day as directed by your doctor. This will make sure that it works properly in controlling your asthma or COPD.

If your asthma or breathing gets worse tell your doctor straight away. You may feel more wheezy, your chest may feel tight more often or you may need to use more of your fast acting ‘reliever’ medicine. If any of these happen, you should continue to take SALFLUMIX EASYHALER but do not increase the number of puffs you take. Your chest condition may be getting worse and you could become seriously ill. See your doctor as you may need additional treatment.

How to use SALFLUMIX EASYHALER

SALFLUMIX EASYHALER is for inhalation through the mouth only.

SALFLUMIX EASYHALER is easy to use. Read through these instructions first: they tell you what you should do and what to look out for.

Unpack the inhaler

Take the inhaler out of its packaging. It comes in a laminate pouch to keep the powder dry. Only take it out of the pouch when you are ready to start using it.

The inhaler should come with a dust cap on the mouthpiece. (Figure 1). The carton will also include a protective cover.

Figure 1

After removal from the laminate pouch, you must fit the inhaler into its protective cover which helps improve the durability of the product. To fit the inhaler into the protective cover, open up the protective cover (Figure 2a). Ensure the dustcap (dark purple/blue cap) covers the mouth-piece of inhaler (this stops the inhaler going off by accident) before inserting the inhaler into the protective cover. Close the protective cover until you hear a click to ensure tight seal

Figure 2a

The inhaler should remain inside the protective cover at all times until dosing. (Figure 2b)

Figure 2b

Discard the SALFLUMIX EASYHALER 250/50 inhaler 1 month after removal from the laminate pouch and the SALFLUMIX EASYHALER 500/50 inhaler 2 months after removal from the laminate pouch. The inhaler label includes a space for you to write the date of when you should discard the inhaler.

How to take a dose from SALFLUMIX EASYHALER

  1. Shake
  • Remove the dust cap.
  • Hold the inhaler upright, gripping it between your finger and thumb
  • Shake the device vigorously up and down three to five times. This is to make sure the powder flows properly and gives the correct dose (Figure 3).

Figure 3

  • Make sure you shake it up and down and you do not click it while you shake it.
  1. Click
  • Make sure the dust cap is not on the inhaler, it will stop you clicking it.
  • Still holding the inhaler upright, squeeze until you hear a click, and let it click back again. This delivers powder into the inhalation channel inside the mouthpiece (Figure 4).

Figure 4

  1. Inhale

In the sitting or standing position

  • Breathe out normally
  • Place the mouthpiece in your mouth between your teeth and close your lips tightly around the mouthpiece to make a good seal (Figure 5).

Figure 5

  • Make sure the whole mouthpiece is well inside your mouth, so the powder does not go on your teeth
  • Take a strong and deep breath in
  • Take the inhaler out of your mouth and hold your breath for about 5 seconds or for as long as it is comfortable, then breathe out gently away from the inhaler.
  • Do not breathe out into the inhaler. This is important: it could clog up the inhaler. If you breathed out into the inhaler, see section “If you have problems using the inhaler”

If you have problems using the inhaler

  • Do not rush things. It is important to breathe normally. Practice a few times, in front of the mirror if this helps.
  • If you click the inhaler by accident, or if you might have clicked it more than once, or if you breathe out into it, tap the mouthpiece to empty the powder onto a table top, or the palm of your hand (Figure 6). This ensures proper dosing. Then start again with steps 1, 2 and 3.

Figure 6

If you are to take a second inhalation

  • Start again with steps 1, 2 and 3 (Note that you need to shake the device again as instructed in step 1).

After you have used the inhaler

  • Put the dust cap back on the mouthpiece and close the protective cover.
  • Rinse your mouth with water and spit it out after you use SALFLUMIX EASYHALER.

Cleaning the Easyhaler

  • Clean the Easyhaler's mouthpiece at least once a week with a dry cloth. Do not use water: the powder in the Easyhaler is sensitive to moisture. You can take the Easyhaler out of it to wipe it. When you are putting it back into its protective cover, put the dust cap on the mouthpiece to stop it going off accidentally.

Getting a new Easyhaler

  • The inhaler has a dose counter which shows how many doses are left. The counter turns after every fifth actuation (Figure 7). When the numbers go red, there are 20 doses left. If you do not already have a new Easyhaler, contact your doctor for a new prescription. When the counter reaches 0, you need to replace the Easyhaler.

Figure 7

For more information on how to use SALFLUMIX EASYHALER please visit www.orionpharma.com.au/patient.

If you forget to use SALFLUMIX EASYHALER

SALFLUMIX EASYHALER should be used regularly at the same time each day.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

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

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

If you use too much SALFLUMIX EASYHALER

If you think that you have used too much SALFLUMIX EASYHALER, you may need urgent medical attention.

You should immediately:

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

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

The most common symptoms that may occur if you use too much SALFLUMIX EASYHALER are trembling, headache, breathing faster than usual a rapid heartbeat or increased levels of blood sugar.

5. What should I know while using SALFLUMIX EASYHALER?

Things you should do

Remind any doctor, dentist or pharmacist you visit that you are using SALFLUMIX EASYHALER.

If you are going to have surgery, tell the surgeon or anaesthetist that you are using 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.

Rinse your mouth after using SALFLUMIX EASYHALER

  • 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 SALFLUMIX EASYHALER. Tell your doctor but do not stop treatment unless told to do so.

Call your doctor straight away if you:

  • experience a change in your vision

Things you should not do

  • Do not stop using this medicine suddenly. If you stop using it suddenly, your condition may worsen, or you may have unwanted side effects. Check with your doctor before you stop using this medicine., if possible, your doctor will gradually reduce the amount you take each day before stopping the medicine completely.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how SALFLUMIX EASYHALER affects you.

Looking after your medicine

  • Store SALFLUMIX EASYHALER below 25°C and protect from moisture.
  • Keep the inhaler in the foil bag until you are ready to start using it.
  • Place the inhaler in the protective cover when you take it out of the foil bag.

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

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

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

Replace your SALFLUMIX EASYHALER 250/50 inhaler 1 month after first opening the foil bag.

Replace your SALFLUMIX EASYHALER 500/50 inhaler 2 months after first opening the foil bag.

If your SALFLUMIX EASYHALER gets damp, you need to replace it with a new one.

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.

Allergic reactions:

You may notice your breathing suddenly gets worse after using SALFLUMIX EASYHALER. You may be very wheezy and cough. You may also notice itching and swelling (usually of the face, lips, tongue, or throat). If you get these effects or if they happen suddenly after using SALFLUMIX EASYHALER, tell your doctor straight away or go to Accident and Emergency at your nearest hospital.

Common Side Effects

  • sore, yellowish, raised patches in
  • the mouth (thrush)
  • soreness in the mouth, throat, or tongue
  • hoarseness
  • headache
  • muscle cramps
  • pains in joints
  • increase in heart rate

Pneumonia (lung infection) has been reported commonly in patients with COPD. Tell your doctor if you notice any of the following symptoms:

  • increase in sputum production
  • change in sputum colour
  • fever, chills
  • increased cough and increased breathing problems.

Uncommon Side Effects

  • skin rash
  • shortness of breath
  • sweating, trembling, feeling
  • nervous or anxious
  • bruising
  • eye problems (e.g. cataract, glaucoma)
  • sleep disturbances

Rare Side Effects

  • behavioural changes, including unusual activity and irritability
  • rounded face
  • slowing of growth in children and adolescents
  • soreness in the oesophagus
  • irregular heartbeat

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

Some side effects can only be found when your doctor does tests from time to time to check your progress, for example:

  • increases in blood sugar (glucose) levels
  • changes in blood pressure
  • loss of bone density
  • reduced potassium levels in the blood
  • changes in the function of the adrenal glands, which make the body's own steroids

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 SALFLUMIX EASYHALER contains

Active ingredients
(main ingredients)		250 or 500 micrograms Fluticasone propionate
and
50 micrograms Salmeterol (as salmeterol xinafoate)
Other ingredients
(inactive ingredients)		Lactose monohydrate
Potential allergensLactose monohydrate
Milk proteins

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

What SALFLUMIX EASYHALER looks like

SALFLUMIX EASYHALER is a dry powder inhaler device that contains a white to yellowish powder. Each inhaler is in a sealed foil bag and packed in a cardboard box together with a protective cover. Each inhaler contains 60 doses.

SALFLUMIX EASYHALER 500/50 (AUST R 338158).

SALFLUMIX EASYHALER 250/50 AUST R 338157).

Who distributes SALFLUMIX EASYHALER

Orion Pharma (Aus) Pty Limited
Level 24, Tower 3
300 Barangaroo Avenue, Sydney, NSW 2000, Australia
Telephone: 1800 861 913

This leaflet was prepared in February 2024.

Published by MIMS April 2024

BRAND INFORMATION

Brand name

Salflumix Easyhaler

Active ingredient

Fluticasone propionate; Salmeterol

Schedule

S4

 

1 Name of Medicine

Fluticasone propionate/ salmeterol xinafoate.

2 Qualitative and Quantitative Composition

Salflumix Easyhaler 250/50.

Each metered dose contains salmeterol xinafoate corresponding to 50 micrograms of salmeterol and 250 micrograms fluticasone propionate. This corresponds to a delivered dose (the dose that leaves the mouthpiece) of salmeterol xinafoate corresponding to 48 micrograms of salmeterol and 238 micrograms fluticasone propionate.

Salflumix Easyhaler 500/50.

Each metered dose contains salmeterol xinafoate corresponding to 50 micrograms of salmeterol and 500 micrograms fluticasone propionate. This corresponds to a delivered dose (the dose that leaves the mouthpiece) of salmeterol xinafoate corresponding to 48 micrograms of salmeterol and 476 micrograms fluticasone propionate.

List of excipients with known effect.

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

3 Pharmaceutical Form

Powder for inhalation in a device metered inhaler.

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. Salflumix Easyhaler is not indicated for the initiation of bronchodilator therapy in COPD.

4.2 Dose and Method of Administration

Salflumix Easyhaler is for inhalation use only.
Salflumix Easyhaler must be used regularly for optimum benefit, even when asymptomatic.
Patients should be regularly assessed by a doctor, so the dose of Salflumix Easyhaler they are receiving remains optimal. Strength of dose should only be increased or decreased on medical advice. For dosages which cannot be achieved with Salflumix Easyhaler (i.e. 100 micrograms fluticasone propionate and 50 micrograms salmeterol) other fixed-dose combination products containing these two active ingredients are available.

Method of administration.

Salflumix Easyhaler is for inhalation only. The inhaler is inspiratory flow-driven, which means that when the patient inhales through the mouthpiece, the substance will follow the inspired air into the airways. A dose counter on the Easyhaler indicates the number of doses left.
Instructions to the patient for the correct use of Salflumix Easyhaler.

Note.

It is important to instruct the patient:
To carefully read the instructions for use in the patient instruction leaflet which is packed together with each inhaler.
To hold the inhaler upright, gripping it between finger and thumb.
To vigorously shake the inhaler up and down 3 to 5 times before actuation.
To actuate (click) the inhaler before inhalation.
To breathe in forcefully and deeply through the mouthpiece to ensure that an optimal dose is delivered to the lungs.
To hold breath after inhaling for at least 5 seconds.
Never to breathe out through the mouthpiece as this will result in a reduction in the delivered dose. Should this happen the patient is instructed to tap the mouthpiece onto a tabletop or the palm of a hand to empty the powder, and then to repeat the dosing procedure.
Never to actuate the device more than once without inhalation of the powder. Should this happen the patient is instructed to tap the mouthpiece onto a tabletop or the palm of a hand to empty the powder, and then to repeat the dosing procedure.
To always replace the dust cap on to the mouthpiece of the inhaler after use to prevent accidental actuation of the device, which could result in either overdosing or under dosing the patient when subsequently used.
To ensure that the inhaler closed with the dust-cap is always enclosed inside the protective cover unless it is needed for dosing. This helps improve the durability of the product.
To rinse the mouth out with water and/or brush teeth after inhaling the maintenance dose to minimise the risk of oropharyngeal thrush.
Water should never be used for cleaning the inhaler because the powder is sensitive to moisture.
To replace Salflumix Easyhaler when the counter reaches zero even though powder could still be observed within the inhaler.
For more detailed instructions for use refer to the patient instruction leaflet.

Dose.

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 Salflumix Easyhaler 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 100/50 micrograms to 500/50 micrograms fluticasone propionate/salmeterol twice daily.

Salflumix Easyhaler.

One inhalation of 250 micrograms fluticasone propionate and 50 micrograms salmeterol twice daily; or
One inhalation of 500 micrograms fluticasone propionate and 50 micrograms salmeterol twice daily.
The recommended dose for initiation of maintenance therapy in moderate persistent asthma is 100/50 micrograms fluticasone propionate/salmeterol twice daily. In these cases, other similar fixed-dose combination products containing these two active ingredients are available. Once control of asthma is attained treatment should be reviewed and consideration given as to whether patients should be stepped down to an inhaled corticosteroid alone. Regular review of patients as treatment is stepped down is important.
Paediatric patients. Salflumix Easyhaler should not be used in children younger than 12 years.

COPD.

Adults.

The recommended dose is 250/50 micrograms or 500/50 micrograms fluticasone propionate/salmeterol twice daily.
One inhalation 500/50 micrograms twice daily; or
One inhalation 250/50 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; Section 4.2 Dose and Method of Administration).

Special patient groups.

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

4.3 Contraindications

Salflumix Easyhaler is contraindicated in patients with a history of hypersensitivity to any ingredients of the preparation (see Section 2 Qualitative and Quantitative Composition; Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

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.
Salflumix Easyhaler 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 Salflumix Easyhaler 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, Salflumix Easyhaler should be administered with caution in patients with active or quiescent pulmonary tuberculosis.
Salflumix Easyhaler 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, Salflumix Easyhaler 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, Salflumix Easyhaler 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 Salflumix Easyhaler therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy.
Salflumix Easyhaler 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. Salflumix Easyhaler 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.
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.
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).
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. Salflumix Easyhaler 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.

Salflumix Easyhaler should not be used in children younger than 12 years.
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.

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 5,362 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 nonfluticasone 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 radiolabelled 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

Salflumix Easyhaler is unlikely to produce an effect.

4.8 Adverse Effects (Undesirable Effects)

As Salflumix Easyhaler 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.

Postmarketing 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 Salflumix Easyhaler, fluticasone and/or salmeterol is given below:
It is not recommended that patients receive higher than approved doses of Salflumix Easyhaler. 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-2adrenergic 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 Salflumix Easyhaler 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 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Salflumix Easyhaler 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. Salflumix Easyhaler 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 (100/50 micrograms, 250/50 airways disease and asthma. Six studies of 12 or 28 weeks 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 100/50 micrograms dose strength (338 patients), two the 250/50 micrograms dose strength (264 patients) and one the 500/50 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 100/50 micrograms and 250/50 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 100/50 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 500/50 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-centre asthma research trial (SMART).

The Salmeterol Multi-centre 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.
Chronic obstructive pulmonary disease (COPD). Three randomised, double blind, placebo-controlled trials have investigated the safety and efficacy of fluticasone propionate/salmeterol in the treatment of patients with COPD. The studies used two fluticasone propionate/salmeterol dose strengths (250/50 micrograms and 500/50 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 500/50 micrograms was superior by a clinically significant degree only for dyspnoea vs salmeterol alone. In addition, fluticasone propionate/salmeterol 250/50 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 500/50 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 Salflumix Easyhaler 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.
The absolute bioavailability of a single dose of inhaled fluticasone propionate in healthy subjects varies between approximately 5 to 11% of the nominal dose depending on the inhalation device used.

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 picogram/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 t½ 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 nanogram/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, co-administration 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 coadministered have been conducted.

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 (leiomyomas and possibly leiomyosarcomas) 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 (which contains small amounts of milk protein).

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

Store below 25°C. Protect from moisture.
After removal from the foil bag, the Salflumix Easyhaler should be placed into the protective cover and remain enclosed inside the protective cover at all times until dosing.
The Salflumix Easyhaler 250/50 inhaler should be discarded 1month after first opening the foil bag.
The Salflumix Easyhaler 500/50 inhaler should be discarded 2 months after first opening the foil bag.

6.5 Nature and Contents of Container

Each carton contains one Easyhaler multiple dose powder inhaler sealed in a foil bag and a protective cover. Each inhaler contains 60 doses.

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 propionate.

Fluticasone propionate is a white to off-white powder. It is freely soluble in dimethyl sulfoxide and dimethylformamide, sparingly soluble in acetone, dichloromethane, ethyl acetate and chloroform, slightly soluble in methanol and 95% ethanol, and practically insoluble in water.
Chemical name: S-Fluoromethyl 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17 α-propionyloxy-androsta-1, 4-diene-17β-carbothioate.

Chemical structure.


Molecular formula: C25H31F3O5S.
Molecular weight: 500.6.

CAS number.

80474-14-2.

Salmeterol (as xinafoate).

Salmeterol xinafoate is a white to off-white crystalline powder. It is freely soluble in methanol, slightly soluble in ethanol, chloroform, and isopropanol, and sparingly soluble in water.
Chemical name: (±)-4-Hydroxy-α1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-m-xylene-α,α'-diol 1-hydroxy-2-naphthoate (salt).

Chemical structure.


Molecular formula: C25H37NO4.C11H8O3.
Molecular weight: 603.8.

CAS number.

94749-08-3.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes