Consumer medicine information

Serevent Accuhaler

Salmeterol

BRAND INFORMATION

Brand name

Serevent Accuhaler

Active ingredient

Salmeterol

Schedule

SUMMARY CMI

SEREVENT ACCUHALER

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 SEREVENT ACCUHALER?

SEREVENT ACCUHALER contains the active ingredient salmeterol xinafoate. SEREVENT ACCUHALER is used to keep the breathing tubes in your lungs open and relieves the symptoms of asthma and other chest conditions.

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

2. What should I know before I use SEREVENT ACCUHALER?

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

3. What if I am taking other medicines?

Some medicines may interfere with SEREVENT ACCUHALER 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 take SEREVENT ACCUHALER?

For adults: the usual dose for asthma and COPD is one blister twice daily. If you have asthma, your doctor may tell you to take two blisters twice daily if necessary
For children 4 years or older: one blister twice daily for asthma

More instructions can be found in Section 4. How do I take SEREVENT ACCUHALER? in the full CMI.

5. What should I know while using SEREVENT ACCUHALER?

Things you should do	Remind any Healthcare Professional (HCP) you visit that you are using SEREVENT ACCUHALER Tell your doctor if you find your SEREVENT ACCUHALER does not help your breathing as much as usual Tell your doctor if you find your SEREVENT ACCUHALER does not last as long as usual
Things you should not do	Do not stop using this medicine suddenly Do not use SEREVENT ACCUHALER to treat any other complaints unless your doctor says it is safe to do so Do not give SEREVENT ACCUHALER to anyone else, even though their symptoms may sound similar to yours
Driving or using machines	Be careful driving or operating machinery until you know how SEREVENT ACCUHALER affects you.
Looking after your medicine	Store below 30°C Store in original packaging

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

6. Are there any side effects?

Side effects which have been reported include tremor, headache and muscle cramps.

Serious side effects include allergic reaction and heart palpitations.

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

SEREVENT ACCUHALER

Active ingredient: salmeterol xinafoate

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using SEREVENT ACCUHALER?

SEREVENT ACCUHALER contains the active ingredient salmeterol xinafoate. SEREVENT ACCUHALER is a bronchodilator. It keeps the breathing tubes in your lungs open and relieves the symptoms of asthma and other chest conditions.

SEREVENT ACCUHALER is used to help you to breathe more easily. SEREVENT ACCUHALER gives relief, for up to twelve hours, from chest tightness or wheeze due to asthma, or other chest conditions in adults namely chronic obstructive pulmonary disease (COPD).

The medicine in SEREVENT ACCUHALER does not start working as quickly as a 'reliever' medicine such as VENTOLIN/salbutamol. SEREVENT ACCUHALER should not be used to relieve a sudden attack of breathlessness or wheezing. If you get this sort of attack, you must use a quick-acting inhaler (such as VENTOLIN/salbutamol).

2. What should I know before I use SEREVENT ACCUHALER?

Warnings

Do not use SEREVENT ACCUHALER if:

you are allergic to 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

Check with your doctor if you:

have any other medical conditions
- thyroid conditions
- heart conditions
- diabetes
- high blood pressure
take any medicines for any other condition
have been diagnosed with an intolerance to some sugars, or to milk protein
have had to stop taking other asthma medicines
feel your asthma is not stable, or is getting worse

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.

It is important that your asthma or chest condition is managed well during pregnancy and you should not stop your medicine without asking your doctor.

3. What if I am taking other medicines?

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

Some medicines may interfere with SEREVENT ACCUHALER and affect how it works.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect SEREVENT ACCUHALER.

4. How do I take SEREVENT ACCUHALER?

How much to take

for adults:
- the usual dose for asthma and COPD is one blister twice daily. If you have asthma, your doctor may tell you to take two blisters twice daily if necessary
for children 4 years or older:
- one blister twice daily for asthma
follow the instructions provided and use SEREVENT ACCUHALER until your doctor tells you to stop

When to take SEREVENT ACCUHALER

SEREVENT ACCUHALER should be used regularly every day, twice daily, in the morning and in the evening

How to use SEREVENT ACCUHALER

SEREVENT ACCUHALER has a dose counter which tells you how many doses are left. When you have reached the last five doses, the numbers appear in red

If you forget to use SEREVENT ACCUHALER

SEREVENT ACCUHALER should be used regularly at the same time each day. If you miss your dose at the usual time, do not worry. Just take the next dose at the normal time.

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

If you use too much SEREVENT ACCUHALER

If you think that you have used too much SEREVENT ACCUHALER, you may need urgent medical attention.

If you take more blisters by mistake, your heart may beat faster than usual, you may get a headache, or you may feel shaky and tense.

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.

5. What should I know while using SEREVENT ACCUHALER?

Things you should do

If you have an asthma attack, use your 'reliever' medicine, not your SEREVENT ACCUHALER.

Call your doctor straight away if you:

find your SEREVENT ACCUHALER does not help your breathing as much as usual
find your SEREVENT ACCUHALER does not last as long as usual

You will need to use a quick-acting inhaler medicine and tell your doctor as soon as possible. These may be signs that your asthma or chest condition is getting worse.

Remember, if you have asthma, you should also use your long-acting inhaler medicine (like an inhaled corticosteroid) regularly every day as your doctor has told you.

Remind any doctor, dentist or pharmacist you visit that you are using SEREVENT ACCUHALER.

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

Things you should not do

do not stop using this medicine suddenly
do not use SEREVENT ACCUHALER to treat any other complaints unless your doctor says it is safe to do so
do not give SEREVENT ACCUHALER to anyone else, even though their symptoms may sound similar to yours

Driving or using machines

Be careful before you drive or use any machines or tools until you know how SEREVENT ACCUHALER affects you.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

store below 30°C
store in original packaging

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

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

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

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date or if the packaging is torn or shows signs of tampering.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effects

What to do

Nervous system disorders:

tremor
headache

Musculoskeletal and connective tissue disorders:

muscle cramps
joint pain

Speak to your doctor if you have any of these less serious side effects and they worry you.

Less serious side effects that require medical intervention. Please consult your doctor if you experience any of the following:

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

Contact your doctor if you experience any of these less serious side effects.

Serious side effects

Serious side effects

What to do

Immune system disorders and allergic reactions:

Symptoms of an allergic reaction usually include some or all of the following:
- shortness of breath
- wheezing, coughing or difficulty breathing
- swelling of the face, lips, tongue or other parts of the body (angioedema)
- rash, itching, redness or hives on the skin (urticaria)
- suddenly feeling weak or light headed (may lead to collapse or loss of consciousness)

Cardiac disorders:

palpitations
irregular or fast heartbeat

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor 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 SEREVENT ACCUHALER contains

Active ingredient (main ingredient)	salmeterol xinafoate
Other ingredients (inactive ingredients)	lactose monohydrate (contains milk protein)
Potential allergens	Lactose monohydrate (contains milk protein)

Each blister (dose) contains 50 micrograms of the active ingredient salmeterol xinafoate.

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

What SEREVENT ACCUHALER looks like

SEREVENT ACCUHALER is a green-coloured plastic device which contains a foil strip inside. The foil strip has 28 or 60 blisters (or pockets) which contain your medicine (AUST R 53775).

Who distributes SEREVENT ACCUHALER

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

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

This leaflet was prepared in March 2025

Version 3.0

Published by MIMS June 2025

BRAND INFORMATION

Brand name

Serevent Accuhaler

Active ingredient

Salmeterol

Schedule

1 Name of Medicine

Salmeterol xinafoate.

2 Qualitative and Quantitative Composition

Serevent Accuhaler is a moulded plastic device containing a foil strip with regularly placed blisters. Each blister contains 50 microgram of salmeterol, as salmeterol xinafoate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for inhalation.

4 Clinical Particulars

4.1 Therapeutic Indications

Adults.

Salmeterol is suitable for long-term regular treatment of reversible airways obstruction in asthma (including nocturnal asthma and exercise induced asthma), in patients who are receiving inhaled or oral corticosteroids. It should not be used in patients whose asthma can be managed by occasional use of short acting inhaled beta-2 agonists.
Salmeterol also provides long lasting (12 hour) bronchodilation for the reversible component of airways obstruction due to chronic obstructive pulmonary disease (COPD).

Children aged 4 years and over.

Long-term regular treatment of reversible airways obstruction in asthma (including nocturnal asthma and exercise induced asthma), in patients who are receiving inhaled or oral corticosteroids. It should not be used in patients whose asthma can be managed by occasional use of short acting inhaled beta-2 agonists.

4.2 Dose and Method of Administration

In order to gain full therapeutic benefit, regular usage of salmeterol is recommended in the treatment of reversible airways obstruction. The full benefits will be apparent after the first few doses of the drug. The bronchodilator effects of salmeterol usually last for 12 hours; this is particularly useful in the treatment of nocturnal symptoms in asthma and COPD and in the management of exercise induced asthma. In the management of exercise induced asthma, it is not appropriate to use salmeterol immediately before exercise as the onset of action of salmeterol occurs usually in 10-30 minutes and the full benefit may only occur after a longer period of time or with repeated doses.
With salmeterol therapy, the requirement for other symptomatic bronchodilator therapy is usually reduced and can sometimes be stopped. If symptoms persist, patients should take a short acting inhaled beta-2 agonist (e.g. salbutamol) for relief, but this need is usually an indication that control of their airways obstruction is suboptimal and that further treatment should be considered. This may involve treatment with other medications or increased doses of current medications.
As there may be adverse effects associated with excessive dosing, the dosage or frequency of administration should only be increased on medical advice. Patients should be instructed not to take additional doses of salmeterol to treat symptoms arising between the regular dosing intervals but to take a short acting inhaled beta-2 agonist.
See Section 2 Qualitative and Quantitative Composition for further information.

Adults.

Serevent Accuhaler is administered by the inhaled route only.
The usual dose for asthma and COPD is one inhalation (50 microgram of salmeterol) twice daily.
In asthma patients with more severe airways obstruction, up to 2 inhalations (2 x 50 microgram of salmeterol) twice daily may be required.

Children aged 4 years and over.

Accuhaler.

One inhalation (50 microgram of salmeterol) twice daily.
There are insufficient clinical data at present to recommend the use of salmeterol in children under 4 years of age. Data from controlled clinical trials beyond 12 months are limited.

Elderly.

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

Impaired renal function.

In patients with impaired renal function there is no need to adjust the dose.

4.3 Contraindications

Hypersensitivity to any ingredient of the preparation (see Section 2 Qualitative and Quantitative Composition; Section 6.1 List of Excipients).
Contraindicated in patients with severe milk protein allergy.

4.4 Special Warnings and Precautions for Use

The management of asthma should normally follow a stepwise programme, and patient response should be monitored clinically and by lung function tests.

Corticosteroids.

Salmeterol is not a replacement for oral or inhaled corticosteroids. Its use is complementary to them. Patients must be warned not to stop steroid therapy and not to reduce it without medical advice, even if they feel better on salmeterol. Any change in corticosteroid dosage should be made only after clinical evaluation.
Salmeterol is not a substitute for inhaled or oral corticosteroids. When salmeterol treatment is initiated in patients with asthma or COPD, corticosteroids should not be stopped or reduced.
In asthma patients not already receiving anti-inflammatory therapy, this should be initiated when starting salmeterol.

Acute symptoms.

Salmeterol is not designed to relieve acute asthmatic symptoms, for which an inhaled short acting bronchodilator (e.g. salbutamol) is required. Patients should be advised to have such rescue medication available. Salmeterol should not be initiated in patients with significantly worsening or acutely deteriorating asthma.
Salmeterol should not be used to treat acute symptoms of asthma. It is crucial to inform patients of this and prescribe a short acting inhaled beta-2 agonist for this purpose and to warn them that increasing inhaled beta-2 agonist use is a signal of deteriorating asthma or COPD.
As salmeterol has a slower onset of action, a faster acting beta-2 agonist should be used when rapid bronchodilator action is required.

Deterioration.

Sudden and progressive deterioration in asthma control is potentially life threatening and consideration should be given to starting or increasing corticosteroid therapy. In patients at risk, daily peak flow monitoring may be instituted. Increasing use of bronchodilators, in particular short acting inhaled beta-agonists to relieve symptoms, indicates deterioration of asthma control. If patients find that short acting relief bronchodilator treatment becomes less effective or they need more inhalations than usual, medical attention must be sought. In this situation, patients should be reassessed and consideration given to the need for increased anti-inflammatory therapy (e.g. higher doses of inhaled corticosteroids or a course of oral corticosteroids). Severe exacerbations of asthma must be treated in the normal way with nebulised or parenteral bronchodilators and parenteral corticosteroids, together with other supportive measures. Patients should be advised to have such rescue medication available.
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.
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).
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.
Salmeterol should be administered with caution in patients with thyrotoxicosis.
As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. If that happens, a short-acting inhaled bronchodilator should be given immediately. Serevent should be discontinued and alternative therapy instituted (see Section 4.8 Adverse Effects (Undesirable Effects)).
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 (see Section 4.8 Adverse Effects (Undesirable Effects)).
Cardiovascular effects, such as increases in systolic blood pressure and heart rate, may occasionally be seen with all sympathomimetic drugs, especially at higher than therapeutic doses. For this reason, 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, salmeterol should be used with caution in patients predisposed to low levels of serum potassium.

Use in the elderly.

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

Paediatric use.

There are insufficient clinical data at present to recommend the use of salmeterol in children under 4 years of age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Both nonselective and selective beta-blockers should be avoided in patients with reversible obstructive airways disease, unless there are compelling reasons for their use.
Coadministration of ketoconazole and salmeterol resulted in a significant increase in plasma salmeterol exposure (1.4-fold C_max 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.

No data available.
(Category B3)
There are no adequate and well controlled studies of salmeterol in pregnant women. The effect of salmeterol on human pregnancy is unknown. As with any medicine, use during pregnancy should be considered only if the expected benefit to the mother is greater than any possible risk to the foetus.
Studies in rats showed slight retardation of ossification and prolongation of gestation at oral doses above 0.5 mg/kg/day. In rabbits, cleft palate and other fetal abnormalities were observed at maternal doses above 0.6 mg/kg/day. These effects are similar to those observed with some other beta-2 agonists, and occurred at maternal plasma levels substantially higher than those that occur with therapeutic use. Extensive experience with other beta-2 agonists has provided no evidence that such effects are relevant for women receiving clinical doses.
Plasma levels of salmeterol after inhaled therapeutic doses are negligible and, therefore, levels in milk should be correspondingly low. Nevertheless, as there is no experience of the use of salmeterol in nursing mothers, its use in such circumstances should only be considered if the expected benefit to the mother is greater than any possible risk to the infant.
Studies in lactating animals support the view that salmeterol is likely to be secreted in only very small amounts into breast milk.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and very rare (< 1/10,000) including isolated reports. Common and uncommon events were generally determined from clinical trial data. The incidence of placebo was not taken into account. Very rare events were generally determined from postmarketing spontaneous data.
The following frequencies are estimated at the standard dose of 50 microgram twice daily. Frequencies at the higher dose of 100 microgram twice daily have also been taken to account where appropriate.

Immune system disorders.

Hypersensitivity reactions. Uncommon: rash.
Very rare: anaphylactic reactions including oedema and angioedema, bronchospasm and anaphylactic shock.

Metabolism and nutrition disorders.

Very rare: hyperglycaemia.

Nervous system disorders.

Common: tremor and headache (see Section 4.4 Special Warnings and Precautions for Use).
The pharmacological side effects of beta-2 agonist treatment, such as tremor and headache have been reported, but tend to be transient and may reduce with regular therapy. Tremor occurs more commonly when administered at doses higher than 50 microgram twice daily.

Cardiac disorders.

Common: palpitations (see Section 4.4 Special Warnings and Precautions for Use).
Uncommon: tachycardia.
Tachycardia occurs more commonly when administered at doses higher than 50 microgram twice daily.
Very rare: cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia and extrasystoles.
Peripheral vasodilatation and a compensatory small increase in heart rate may occur in some patients.

Respiratory, thoracic and mediastinal disorders.

Very rare: oropharyngeal irritation and paradoxical bronchospasm (see Section 4.4 Special Warnings and Precautions for Use).

Musculoskeletal and connective tissue disorders.

Common: muscle cramps.
Very rare: arthralgia.

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 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.
If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Further management should be as clinically indicated or as recommended by the Poison Information Centre.
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.

Mode of action.

Salmeterol belongs to a new class of selective long acting beta-2 adrenoceptor agonists 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, from human lung fragments, of mast cell mediators, such as histamine, leukotrienes and prostaglandin D₂. 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 hyper-responsiveness. These properties indicate that salmeterol has additional nonbronchodilator activity, but the full clinical significance is not yet clear. The mechanism is different from the anti-inflammatory effect of corticosteroids, which should not be stopped or reduced when salmeterol is prescribed.

Clinical trials.

Asthma.

Adults.

Approximately 2,500 adults with mild to severe asthma were treated with salmeterol in randomised, double blind studies in the clinical trial program.
667 adults with mild to moderate asthma (PEF or FEV₁ 60-90%, and reversibility > 15%) were entered in a 3 month pivotal study. Compared to patients who received salbutamol 200 microgram four times daily (qid), patients on salmeterol 50 microgram twice daily (bd) (n = 334) had significantly improved morning PEF (differences of 31 to 36 L/min) and evening PEF (differences of 9 to 14 L/min). Symptom scores and the requirement for "rescue" bronchodilator medication were also significantly reduced from the first week of treatment onwards.
Similar results were seen in a study comparing salmeterol 50 microgram bd with salbutamol 400 microgram qid using dry powder inhalers.
In 2 separate studies, salmeterol 50 microgram bd also proved more effective than inhaled salbutamol taken on an "as required" basis.
In patients with moderate to severe asthma (n = 283, FEV₁ or PEF < 50% of predicted normal value, with FEV₁ reversibility > 15%), salmeterol 100 microgram bd produced significant improvement in morning and evening PEF over salmeterol 50 microgram bd. The higher dose also improved daytime symptoms and reduced bronchodilator use significantly more than 50 microgram bd. Other symptoms were equally well controlled on 50 microgram bd.
In all these studies, salmeterol improved nocturnal asthma measures, such as number of nocturnal awakenings and percentage of nights with no awakenings.

Children.

831 children with asthma, aged 4 to 16, were entered in a total of 8 clinical trials. On entry, they had FEV₁ > 60% or PEF diurnal variation > 15%, with > 15% reversibility in FEV₁ or PEF.
Salmeterol 50 microgram bd significantly improved lung function (morning PEF +17 L/minute; evening PEF +24 L/min), and reduced daytime symptoms, compared to placebo with p.r.n. salbutamol.
Compared to salbutamol 200 microgram bd, salmeterol 50 microgram bd achieved significantly greater asthma control with respect to morning and evening PEF (+14 L/minute and +17 L/minute, respectively with dry powder inhaler, and +9 L/minute and +8 L/minute, respectively with the metered dose inhaler).
Salmeterol 50 microgram bd protected against exercise induced bronchoconstriction for at least 9 hours in children and 12 hours in adults.
The studies in both adult and paediatric patients showed that improvements in lung function were sustained over a 12 month period.
Serevent Inhaler and Accuhaler were demonstrated to be clinically equivalent.
COPD. In 3 randomised double blind studies, a total of 542 adult patients were treated with salmeterol. Two doses of salmeterol were compared against placebo. At entry, patients had between 5-15% airway reversibility, FEV₁ < 70%, and were either current or past smokers. They were either diagnosed as COPD, or had symptoms (cough/ sputum) for > 3 months/year in 2 consecutive years.
Over a 16 week treatment period, compared to placebo, 447 patients on salmeterol 50 microgram bd had significantly improved median symptom scores during the day and night, increased number of symptom free nights, reduced use of bronchodilator rescue medication, and improved FEV₁ and FVC. Salbutamol was available as rescue medication in all groups.
No significant treatment differences were seen in exacerbation rates or sputum production. No significant treatment differences were detected with respect to distance walked in a 6 minute period; however, the patients experienced significantly less breathlessness (Borg scale). A similar result was seen in a separate study on the effect of treatment on exercise capacity.
In the 16 week study, the improvements produced by salmeterol 50 microgram bd resulted in significant quality of life gains for COPD patients. Both investigators' and patients' assessment of effectiveness consistently favoured salmeterol 50 microgram bd over placebo.
The incidence of drug related adverse events was similar for placebo and salmeterol 50 microgram bd. There is no experience with salmeterol in COPD patients beyond 16 weeks.
Post-market safety study. Data from a large US study that compared the safety of salmeterol inhaler 50 microgram twice daily or placebo added to usual asthma therapy showed no difference between treatments for the primary endpoint which was serious respiratory related episodes or serious asthma related episodes (including deaths). However, when asthma related deaths were analysed alone, there was a small but significant increase in patients receiving salmeterol versus those on placebo (13 out of 13,176 versus 3 out of 13,179 over 28 weeks). In this study the overall death rate was lower than expected, hence it is not clear if any differences seen were due to treatment or other confounding factors. Subgroup analyses revealed no significant difference in respiratory or asthma related episodes in Caucasian patients, but the data suggest the risk for respiratory related episodes (20 versus 5), asthma related episodes (19 versus 4) and asthma related death (7 versus 1) may be greater for African American patients treated with salmeterol (n = 2,366) compared to those treated with placebo (n = 2,319). Patients on salmeterol who did not receive inhaled corticosteroids as part of their usual therapy at the start of the study experienced a greater number of asthma related deaths compared to those taking placebo (9 out of 7,049 versus 0 out of 7,041). There were no significant differences between the salmeterol and placebo treatment groups among patients who were receiving inhaled corticosteroids at the start of the study.

5.2 Pharmacokinetic Properties

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 t_1/2 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 nanogram/mL. These concentrations are up to 1,000-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 microgram 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 C_max and 15-fold AUC). There was no increase in salmeterol accumulation with repeat dosing. Three subjects were withdrawn from salmeterol and ketoconazole coadministration due to QTc prolongation or palpitations with sinus tachycardia. The increase in the QTc interval observed with the coadministration 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).

Metabolism.

Aliphatic hydroxylation appears to be the major route of metabolism in humans.

Excretion.

Excretion is predominantly through the faeces and to a lesser extent urine.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Oral administration of salmeterol xinafoate 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 milk protein) (see Section 4.3 Contraindications).

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 30°C. Store in a dry place.

6.5 Nature and Contents of Container

Serevent Accuhaler is a moulded plastic device containing a foil strip with 28 or 60 regularly placed blisters. Each blister strip consists of a formed base foil (polyamide film/aluminium foil/PVC film) with a peelable foil laminate lid (white paper/polyethylene terephthalate film/aluminium foil).

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

Chemical Name: 4-Hydroxy-*'-[[[6-(4-phenylbutoxy) hexyl]amino]-methyl]- 1,3-benzenedimethanol, 1-hydroxyl-2-naphthoate.

Chemical structure.

CAS number.

94749-08-3.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

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Serevent Accuhaler

Salmeterol

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BRAND INFORMATION

Serevent Accuhaler 50 mcg/actuation