NOTE TO RECIPIENTS: Research Review publications are supported by product sponsors without which the publication could not continue. To meet legal obligations, the company is required to provide the information about the products that support the Reviews. The Reviews remain independent and Research Review is grateful for the support and/or sponsorship provided.

The prescribing information detailed below has been provided by the companies responsible as the most current data at the date of publication. To ensure this has not changed, please review the full data sheet from the appropriate country of use. These can be obtained from the manufaturing company on the appropriate regulatory body responsible for product review and/or registration.

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SERETIDE ACCUHALER/DISKUSE
Salmeterol/fluticasone propionate

QUALITATIVE AND QUANTITATIVE COMPOSITION
Moulded plastic device containing a foil strip with 28 or 60 regularly placed blisters each containing 50 micrograms of salmeterol as salmeterol xinafoate and 100 micrograms of fluticasone propionate.
Moulded plastic device containing a foil strip with 28 or 60 regularly placed blisters each containing 50 micrograms of salmeterol as salmeterol xinafoate and 250 micrograms of fluticasone propionate.
Moulded plastic device containing a foil strip with 28 or 60 regularly placed blisters each containing 50 micrograms of salmeterol as salmeterol xinafoate and 500 micrograms of fluticasone propionate.

PHARMACEUTICAL FORM
Inhalation powder.

CLINICAL PARTICULARS
Indications
Reversible Obstructive Airways Disease (ROAD)
SERETIDE is indicated in the regular treatment of reversible obstructive airways disease (ROAD), including asthma in children and adults, where use of a combination
(bronchodilator and inhaled corticosteroid) is appropriate.
This may include:
Patients on effective maintenance doses of long-acting beta-agonists and inhaled corticosteroids.
Patients who are symptomatic on current inhaled corticosteroid therapy.
Patients on regular bronchodilator therapy who require inhaled corticosteroids.
Chronic Obstructive Pulmonary Disease (COPD)

SERETIDE is indicated for the regular treatment of chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema.

Dosage and Administration
SERETIDE Accuhaler/Diskus is for inhalation only.
Patients should be made aware that SERETIDE Accuhaler/Diskus must be used regularly for optimum benefit, even when asymptomatic.
Patients should be regularly reassessed by a doctor, so that the strength of SERETIDE they are receiving remains optimal and is only changed on medical advice.

Reversible Obstructive Airways Disease (ROAD)
The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. Where the control of symptoms is maintained with twice daily SERETIDE, titration to the lowest effective dose could include SERETIDE given once daily.
Patients should be given the strength of SERETIDE containing the appropriate fluticasone propionate dosage for the severity of their disease.
If a patient is inadequately controlled on inhaled corticosteroid therapy alone, substitution with SERETIDE at a therapeutically equivalent corticosteroid dose may
result in an improvement in asthma control. For patients whose asthma control is acceptable on inhaled corticosteroid therapy alone, substitution with SERETIDE may
permit a reduction in corticosteroid dose while maintaining asthma control. For further information, please refer to the ‘PharmacodynamicsEsection.

Recommended Doses:-

Adults and adolescents 12 years and older:-
One inhalation (50 micrograms salmeterol and 100 micrograms fluticasone propionate) twice daily.
or
One inhalation (50 micrograms salmeterol and 250 micrograms fluticasone propionate) twice daily.
or
One inhalation (50 micrograms salmeterol and 500 micrograms fluticasone propionate) twice daily.

Adults 18 years and older:-

Doubling the dose of all strengths of SERETIDE in adults for up to 14 days has comparable safety and tolerability to regular twice daily dosing and may be considered
when patients require additional short term (up to 14 days) inhaled corticosteroid therapy as outlined in asthma treatment guidelines.

Children 4 years and older:-
One inhalation (50 micrograms salmeterol and 100 micrograms fluticasone propionate) twice daily.
There are no data available for use of SERETIDE in children aged under 4 years.

Chronic Obstructive Pulmonary Disease (COPD)
For adult patients the recommended dose is one inhalation 50/250 micrograms to 50/500 micrograms salmeterol/fluticasone propionate twice daily.
Special patient groups:-
There is no need to adjust the dose in elderly patients or in those with renal or hepatic impairment.

Contraindications
SERETIDE is contraindicated in patients with a history of hypersensitivity to any of the ingredients (see List of Excipients).

Warnings and Precautions
The management of ROAD should normally follow a stepwise programme and patient response should be monitored clinically and by lung function tests.
SERETIDE Accuhaler/Diskus is not for relief of acute symptoms for which a fast and short-acting 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 SERETIDE has failed to give adequate control of ROAD, 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 with SERETIDE 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. As with all inhaled medication containing corticosteroids, SERETIDE should be administered with caution in patients with active or quiescent pulmonary tuberculosis.

SERETIDE 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, SERETIDE 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, SERETIDE should be used with caution in patients predisposed to low levels of serum potassium.

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods; these effects are much less likely to occur than with oral
corticosteroids (see Overdose). Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important, therefore for ROAD patients, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control is maintained. The possibility of impaired adrenal response should always be borne in mind in emergency and elective situations likely to produce stress and appropriate corticosteroid treatment considered (see Overdose).

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored. Certain individuals can show greater susceptibility to the effects of inhaled corticosteroid than do most patients.

Because of the possibility of impaired adrenal response, patients transferring from oral steroid therapy to inhaled fluticasone propionate therapy should be treated with special care, and adrenocortical function regularly monitored.

Following introduction of inhaled fluticasone propionate, withdrawal of systemic therapy should be gradual and patients encouraged to carry a steroid warning card indicating the possible need for additional therapy in times of stress.

There have been very rare reports of increases in blood glucose levels (see Adverse Reactions) and this should be considered when prescribing to patients with a history of
diabetes mellitus.
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 (see Interactions).

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 3AF 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.

Pregnancy and Lactation
Administration of drugs during pregnancy and lactation should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus or child. There is insufficient experience of the use of salmeterol xinafoate and fluticasone propionate in human pregnancy and lactation.

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
beta2-adrenoreceptor agonist and glucocorticosteroid.
Extensive clinical experience with drugs in these classes has revealed no evidence that the effects are relevant at therapeutic doses. Neither salmeterol xinafoate or fluticasone propionate have shown any potential for genetic toxicity.
Salmeterol and fluticasone propionate concentrations in plasma after inhaled therapeutic doses are very low and therefore concentrations in human breast milk are likely to be correspondingly low. This is supported by studies in lactating animals, in which low drug concentrations were measured in milk. There are no data available for human breastmilk.

Effects on Ability to Drive and Use Machines
There have been no specific studies of the effect of SERETIDE on the above activities, but the pharmacology of both drugs does not indicate any effect.

Adverse Reactions
As SERETIDE contains salmeterol and fluticasone propionate, the type and severity of adverse reactions associated with each of the compounds may be expected. There is no incidence of additional adverse events following concurrent administration of the two compounds.
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 and short-acting inhaled bronchodilator. Salmeterol/fluticasone propionate Accuhaler/Diskus should be discontinued immediately, the patient assessed and
alternative therapy instituted if necessary.

Adverse events which have been associated with salmeterol or fluticasone propionate are given below.
Salmeterol:-
The pharmacological side effects of beta2-agonist treatment, such as tremor, subjective palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.
Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles) may occur, usually in susceptible patients. There have been very rare reports of arthralgia.

Hypersensitivity reactions, including anaphylactic reactions such as oedema and angioedema, bronchospasm and anaphylactic shock have been reported very rarely.
There have also been uncommon reports of rash.
There have been reports of oropharyngeal irritation.
There have been common reports of muscle cramps.
There have been very rare reports of hyperglycaemia.

Fluticasone propionate:-
Hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients. There have been uncommon reports of cutaneous hypersensitivity reactions. There have also been rare reports of hypersensitivity reactions manifesting as angioedema (mainly facial and oropharyngeal oedema), respiratory symptoms (dyspnoea and/or
bronchospasm) and very rarely, anaphylactic reactions.
Both hoarseness and incidence of candidiasis may be relieved by gargling with water after use of salmeterol/fluticasone propionate Accuhaler/Diskus. Symptomatic
candidiasis can be treated with topical anti-fungal therapy whilst still continuing with salmeterol/fluticasone propionate Accuhaler/Diskus.
Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral
density, cataract and glaucoma (see Warnings and Precautions). There have been very rare reports of hyperglycaemia.
There have been very rare reports of anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children).

Salmeterol/fluticasone propionate clinical trials:-
The following undesirable effects were commonly reported:
Hoarseness/dysphonia, throat irritation, headache, candidiasis of mouth and throat and palpitations.
Salmeterol/fluticasone propionate postmarketing:-
There have been uncommon reports of cutaneous hypersensitivity reactions. There have also been rare reports of hypersensitivity reactions manifesting as angioedema (mainly facial and oropharyngeal oedema), respiratory symptoms (dyspnoea and/or bronchospasm) and very rarely, anaphylactic reactions.
There have been very rare reports of anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children).
There have also been very rare reports of hyperglycaemia.

Overdose
The available information on overdose with SERETIDE, salmeterol and/or fluticasone propionate is given below:
The expected symptoms and signs of salmeterol overdosage are those typical of excessive beta2–adrenergic stimulation, including tremor, headache, tachycardia,
increases in systolic blood pressure and hypokalaemia. The preferred antidotes are cardioselective beta-blocking agents, which should be used with caution in patients with
a history of bronchospasm. If SERETIDE therapy has to be withdrawn due to overdose of the beta agonist component of the drug, provision of appropriate replacement
corticosteroid therapy should be considered.
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 SERETIDE 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); observed features have included
hypoglycaemia associated with decreased consciousness and/or convulsions. 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.
It is not recommended that patients receive higher than approved doses of SERETIDE. It is important to review therapy regularly and titrate down to the lowest approved dose at which effective control of disease is maintained (see Dosage and Administration).

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics
SERETIDE clinical trials
Asthma
A large twelve-month study (Gaining Optimal Asthma ControL, GOAL) in 3416 asthma patients compared the efficacy and safety of SERETIDE versus inhaled corticosteroid
alone in achieving pre-defined levels of asthma control. Treatment was stepped-up every 12 weeks until ##‘Total controlEwas achieved or the highest dose of study drug was
reached. Control needed to be sustained for at least 7 out of the last 8 weeks of treatment.
The study showed that:
CONFIDENTIAL
E71% of patients treated with SERETIDE achieved #‘Well-controlledEasthma compared with 59% of patients treated with inhaled corticosteroid alone.
E41% of patients treated with SERETIDE achieved ##‘Total controlEof asthma compared with 28% of patients treated with inhaled corticosteroid alone.
These effects were observed earlier with SERETIDE compared with inhaled corticosteroid alone and at a lower inhaled corticosteroid dose.
The GOAL study also showed that:
EThe rate of exacerbations was 29% lower with SERETIDE compared to inhaled corticosteroid treatment alone.
EAttaining ‘Well controlledEand ‘Totally controlledEasthma improved Quality of Life (QoL). 61% of patients reported minimal or no impairment on QoL, as measured by
an asthma specific quality of life questionnaire, after treatment with SERETIDE compared to 8% at baseline.
#Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung function plus no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy.
##Total control of asthma; no symptoms, no SABA use greater than or equal to 80% predicted lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy.

Two further studies have shown improvements in lung function, percentage of symptom free days and reduction in rescue medication use, at 60% lower inhaled corticosteroid dose with SERETIDE compared to treatment with inhaled corticosteroid alone, whilst the control of the underlying airway inflammation, measured by bronchial biopsy and bronchoalveolar lavage, was maintained.
Additional studies have shown that treatment with SERETIDE significantly improves asthma symptoms, lung function and reduces the use of rescue medication compared to treatment with the individual components alone and placebo. Results from GOAL show that the improvements seen with SERETIDE, in these endpoints, are maintained over at least 12 months.

COPD
Symptomatic COPD patients without restriction to 10% reversibility to a short acting beta2-agonist:-
Placebo-controlled clinical trials, over 6 months, have shown that regular use of both SERETIDE 50/250 and 50/500 micrograms rapidly and significantly improves lung
function, significantly reduced breathlessness and the use of relief medication. There were also significant improvements in health status.

Symptomatic COPD patients who demonstrated less than 10% reversibility to a short acting beta2-agonist:-
Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of SERETIDE 50/500 micrograms rapidly and significantly improves lung function,
significantly reduced breathlessness and the use of relief medication. Over a 12-month period the risk of COPD exacerbations and the need for additional courses of oral
corticosteroids was significantly reduced. There were also significant improvements in health status.
SERETIDE 50/500 micrograms was effective in improving lung function, health status and reducing the risk of COPD exacerbations, in both current and ex-smokers.

Mechanism of action:-
SERETIDE contains salmeterol and fluticasone propionate which have differing modes of action. Salmeterol protects against symptoms, fluticasone propionate improves lung function and prevents exacerbations of the condition. SERETIDE can offer a more convenient regime for patients on concurrent beta-agonist and inhaled corticosteroid
therapy. The respective mechanisms of action of both drugs are discussed below:
Salmeterol:-
Salmeterol is a selective long-acting (12 h) beta2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor.
These pharmacological properties of salmeterol offer more effective protection against histamine-induced bronchoconstriction and produce a longer duration of bronchodilation, lasting for at least 12 h, than recommended doses of conventional short-acting beta2- agonists.
In vitro tests have shown salmeterol is a potent and long-lasting inhibitor of the release, from human lung, of mast cell mediators such as histamine, leukotrienes and
prostaglandin D2.
In man salmeterol inhibits the early and late phase response to inhaled allergen; the latter persisting for over 30 h 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 non-bronchodilator activity but the full clinical significance is not yet clear. This mechanism is different from the antiinflammatory effect of corticosteroids.

Fluticasone propionate:-
Fluticasone propionate given by inhalation at recommended doses has a potent glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms
and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
Daily output of adrenocortical hormones usually remain within the normal range during chronic treatment with inhaled fluticasone propionate, even at the highest recommended doses in children and adults. After transfer from other inhaled steroids, the daily output gradually improves despite past and present intermittent use of oral steroids, thus demonstrating return of normal adrenal function on inhaled fluticasone propionate. The adrenal reserve also remains normal during chronic treatment, as measured by a normal increment on a stimulation test. However, any residual impairment of adrenal reserve from previous treatment may persist for a considerable time and should be borne in mind (see Warnings and Precautions)

Pharmacokinetics
There is no evidence in animal or human subjects that the administration of salmeterol and fluticasone propionate 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 SERETIDE are very low, potential interactions with other substrates and inhibitors of CYP 3A4 cannot be excluded.
Salmeterol:-
Salmeterol acts locally in the lung therefore plasma levels are not an indication of therapeutic effects. In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma due to the low plasma concentrations at therapeutic doses (approximately 200 picograms/ml or less) achieved after inhaled dosing. After regular dosing with salmeterol xinafoate, hydroxynaphthoic acid can be detected in the systemic circulation,
reaching steady state concentrations of approximately 100 nanograms/ml. These concentrations are up to 1000 fold lower than steady state levels observed in toxicity
studies. No detrimental effects have been seen following long-term regular dosing (more than 12 months) in patients with airway obstruction.

An in vitro study showed that salmeterol is extensively metabolised to E hydroxysalmeterol (aliphatic oxidation) by cytochrome P450 3A4 (CYP3A4). However, a repeat dose study with salmeterol and erythromycin in healthy volunteers showed no clinically significant changes in pharmacodynamic effects at 500 mg three times daily
doses of erythromycin.

Fluticasone propionate:-
The absolute bioavailability of inhaled fluticasone propionate in healthy subjects varies between approximately 10 to 30% of the nominal dose depending on the inhalation
device used. In patients with ROAD or COPD a lesser degree of systemic exposure to inhaled fluticasone propionate has been observed. Systemic absorption occurs mainly
through the lungs and is initially rapid then prolonged. The remainder of the inhaled dose may be swallowed but contributes minimally to systemic exposure due to the low
aqueous solubility and pre-systemic metabolism, resulting in oral availability of less than 1%. There is a linear increase in systemic exposure with increasing inhaled dose. The disposition of fluticasone propionate is characterised by high plasma clearance (1150 ml/min), a large volume of distribution at steady-state (approximately 300 l) and a
terminal half-life of approximately 8 h. Plasma protein binding is moderately high (91%). Fluticasone propionate is cleared very rapidly from the systemic circulation,
principally by metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. The renal clearance of fluticasone propionate is negligible
(<0.2%) and less than 5% as the metabolite. Care should be taken when co-administering known CYP3A4 inhibitors, as there is potential for increased systemic exposure to fluticasone propionate.

Special Patient Populations
SERETIDE
Accuhaler/Diskus:
Population pharmacokinetic analysis was performed utilising data for asthmatic subjects (nine clinical studies for FP and five studies for salmeterol) and showed the following:
- Higher FP exposure seen following administration of SERETIDE (50/100 micrograms) compared to FP alone (100 micrograms) in adolescents and adults (ratio 1.52 [90% CI 1.08, 2.13]) and children (ratio 1.20 [90% CI 1.06, 1.37]).
- Higher FP exposure observed in children taking SERETIDE (50/100 micrograms) compared to adolescents and adults (ratio 1.63 [90% CI 1.35, 1.96]).
- The clinical relevance of these findings are not known, however, no differences in HPA axis effects were observed in clinical studies of up to 12 weeks duration
comparing SERETIDE (50/100 micrograms) and FP (100 micrograms) in both adolescents and adults and in children.
- FP exposure was similar at the higher SERETIDE 50/500 microgram dose compared to the equivalent FP dose alone.
- Higher salmeterol exposure was observed in children taking SERETIDE (50/100 micrograms) compared to adolescents and adults (ratio 1.23 [90% CI 1.10, 1.38]).
- The clinical relevance of these findings are not known, however there were no differences observed in cardiovascular effects or reports of tremor between adults,
adolescents and children in clinical studies of up to 12 weeks duration.

Pre-clinical Safety Data
Salmeterol xinafoate and fluticasone propionate 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 beta2-adrenoreceptor agonist and glucocorticosteroid.
In long term studies, salmeterol xinafoate induced benign tumours of smooth muscle in the mesovarium of rats and the uterus of mice. Rodents are sensitive to the formation of these pharmacologically- induced tumours. Salmeterol is not considered to represent a significant oncogenic hazard to man.
Co-administration of salmeterol and fluticasone propionate resulted in some cardiovascular interactions at high doses. In rats, mild atrial myocarditis and focal coronary arteritis were transient effects that resolved with regular dosing. In dogs, heart rate increases were greater after co-administration than after salmeterol alone. No clinically relevant serious adverse cardiac effects have been observed in studies in man. Co-administration did not modify other class-related toxicities in animals.

PHARMACEUTICAL PARTICULARS
List of Excipients
Lactose (which contains milk protein).
Incompatibilities
None reported.
Shelf Life
18 months.

Special Precautions for Storage
Do not store above 30°C.
Store in a dry place.

Nature and Contents of Container
As registered locally.

Instructions for Use/Handling
The Accuhaler/Diskus releases a powder which is inhaled into the lungs. The device is opened and primed by sliding the lever. The mouthpiece is then placed in
the mouth and the lips closed around it. The dose can then be inhaled and the device closed. A dose indicator on the Accuhaler/Diskus indicates the number of doses left.

Instructions for use of your SERETIDE Accuhaler/Diskus
CLOSED
When you take your Accuhaler/Diskus out of its box, it will be in the closed position.
OPENED
A new Accuhaler/Diskus contains 28 or 60 doses individually protected doses of your medicine, in powder form. The dose indicator tells you how many doses are left.
Each dose is accurately measured and hygienically protected. It requires no maintenance - and no refilling.

The dose indicator on top of your Accuhaler/Diskus tells you how many doses are left. Numbers 5 to 0 will appear in RED, to warn you when there are only a few doses left.
The Accuhaler/Diskus is easy to use. When you need a dose, just follow the four simple steps illustrated:-
1. Open.
2. Slide.
3. Inhale.
4. Close.

How your Accuhaler/Diskus works
Sliding the lever of your Accuhaler/Diskus opens a small hole in the mouthpiece and unwraps a dose, ready for you to inhale it. When you close the Accuhaler/Diskus, the
lever automatically moves back to its original position, ready for your next dose when you need it. The outer case protects your Accuhaler/Diskus when it is not in use.
1. Open - How to use the Accuhaler/Diskus.
To open your Accuhaler/Diskus, hold the outer case in one hand and put the thumb of your other hand on the thumbgrip. Push your thumb away from you as far as it will go.
2. Slide.
Hold your Accuhaler/Diskus with the mouthpiece towards you. Slide the lever away from you, as far as it will go - until it clicks. Your Accuhaler/Diskus is now ready to use.
Every time the lever is pushed back, a dose is made available for inhaling. This is shown by the dose counter. Do not play with the lever as this releases doses which will be
wasted.
3. Inhale
- Before you start to inhale the dose, read through this section carefully.
- Hold the Accuhaler/Diskus away from your mouth. Breathe out as far as is comfortable. Remember - never breathe into your Accuhaler/Diskus.
- Put the mouthpiece to your lips. Breathe in steadily and deeply - through the Accuhaler/Diskus, not through your nose.
- Remove the Accuhaler/Diskus from your mouth.
- Hold your breath for about 10 seconds, or for as long as is comfortable.
- Breathe out slowly.
4. Close
To close your Accuhaler/Diskus, put your thumb in the thumbgrip, and slide the thumbgrip back towards you, as far as it will go.
When you close the Accuhaler/Diskus, it clicks shut. The lever automatically returns to its original position and is reset. Your Accuhaler/Diskus is now ready for you to use
again. If you have been instructed to take two inhalations you must close the Accuhaler/Diskus and repeat stages 1 to 4.

REMEMBER
Keep your Accuhaler/Diskus dry.
Keep it closed when not in use.
Never breathe into your Accuhaler/Diskus.
Only slide the lever when you are ready to take a dose.
Do not exceed the stated dose.
Keep out of reach of children.
Not all presentations are available in every country.
Version number: GDS19/IPI07
Date of issue: 20 June 2006
SERETIDE, ACCUHALER, DISKUS are trademarks of the GlaxoSmithKline group of
companies

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SERETIDE EVOHALERE
Salmeterol/fluticasone propionate

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each single actuation of SERETIDE provides:
Salmeterol xinafoate equivalent to 25 micrograms of salmeterol and 50, 125 or 250 micrograms of fluticasone propionate.

PHARMACEUTICAL FORM
Inhalation aerosol.

CLINICAL PARTICULARS
Indications
Reversible Obstructive Airways Disease (ROAD)
SERETIDE is indicated in the regular treatment of reversible obstructive airways disease (ROAD), including asthma in children and adults, where use of a combination
(bronchodilator and inhaled corticosteroid) is appropriate.
This may include:
Patients on effective maintenance doses of long-acting beta-agonists and inhaled corticosteroids.
Patients who are symptomatic on current inhaled corticosteroid therapy.
Patients on regular bronchodilator therapy who require inhaled corticosteroids.
Chronic Obstructive Pulmonary Disease (COPD)
SERETIDE is indicated for the regular treatment of chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema.

Dosage and Administration
SERETIDE Evohaler is for inhalation only.
Patients should be made aware that SERETIDE Evohaler must be used regularly for optimum benefit, even when asymptomatic.
Patients should be regularly reassessed by a doctor, so that the strength of SERETIDE they are receiving remains optimal and is only changed on medical advice.

Reversible Obstructive Airways Disease (ROAD)
The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. Where the control of symptoms is maintained with twice daily SERETIDE, titration to the lowest effective dose could include SERETIDE given once daily.
Patients should be given the strength of SERETIDE containing the appropriate fluticasone propionate dosage for the severity of their disease. If a patient is inadequately controlled on inhaled corticosteroid therapy alone, substitution with SERETIDE at a therapeutically equivalent corticosteroid dose may result in an improvement in asthma control. For patients whose asthma control is acceptable on inhaled corticosteroid therapy alone, substitution with SERETIDE may permit a reduction in corticosteroid dose while maintaining asthma control. For further information, please refer to the ‘PharmacodynamicsEsection.

Recommended Doses:
Adults and adolescents 12 years and older:-
Two inhalations of 25 micrograms salmeterol and 50 micrograms fluticasone propionate twice daily.
or
Two inhalations of 25 micrograms salmeterol and 125 micrograms fluticasone propionate twice daily.
or
Two inhalations of 25 micrograms salmeterol and 250 micrograms fluticasone propionate twice daily.

Adults 18 years and older:-
Doubling the dose of all strengths of SERETIDE in adults for up to 14 days has comparable safety and tolerability to regular twice daily dosing and may be considered
when patients require additional short term (up to 14 days) inhaled corticosteroid therapy as outlined in asthma treatment guidelines.

Children 4 years and older:-
Two inhalations of 25 micrograms salmeterol and 50 micrograms fluticasone propionate twice daily.
There are no data available for use of SERETIDE in children aged under 4 years.

Chronic Obstructive Pulmonary Disease (COPD)
For adult patients the recommended dose is two inhalations 25/125 micrograms to 25/250 micrograms salmeterol/fluticasone propionate twice daily.
Special patient groups:- There is no need to adjust the dose in elderly patients or in those with renal or hepatic impairment.

Contraindications
SERETIDE is contraindicated in patients with a history of hypersensitivity to any of the ingredients.

Warnings and Precautions
The management of ROAD should normally follow a stepwise programme and patient response should be monitored clinically and by lung function tests.
SERETIDE Evohaler is not for relief of acute symptoms for which a fast and short-acting 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 SERETIDE has failed to give adequate control of ROAD, 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 with SERETIDE 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.

As with all inhaled medication containing corticosteroids, SERETIDE should be administered with caution in patients with active or quiescent pulmonary tuberculosis.
SERETIDE 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, SERETIDE 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, SERETIDE should be used with caution in patients predisposed to low levels of serum potassium.

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods; these effects are much less likely to occur than with oral
corticosteroids (see Overdose). Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma.
It is important, therefore for ROAD patients, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control is maintained.
The possibility of impaired adrenal response should always be borne in mind in emergency and elective situations likely to produce stress and appropriate corticosteroid
treatment considered (see Overdose).
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored.
Certain individuals can show greater susceptibility to the effects of inhaled corticosteroid than do most patients.
Because of the possibility of impaired adrenal response, patients transferring from oral steroid therapy to inhaled fluticasone propionate therapy should be treated with special care, and adrenocortical function regularly monitored.

Following introduction of inhaled fluticasone propionate, withdrawal of systemic therapy should be gradual and patients encouraged to carry a steroid warning card indicating the possible need for additional therapy in times of stress.
There have been very rare reports of increases in blood glucose levels (see Adverse Reactions) and this should be considered when prescribing to patients with a history of
diabetes mellitus.
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 (see Interactions).

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 corticosteroidside-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.

Pregnancy and Lactation
Administration of drugs during pregnancy and lactation should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus or child. There is insufficient experience of the use of salmeterol xinafoate and fluticasone propionate in human pregnancy and lactation.
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
beta2-adrenoreceptor agonist and glucocorticosteroid.
Salmeterol and fluticasone propionate concentrations in plasma after inhaled therapeutic doses are very low and therefore concentrations in human breast milk are likely to be correspondingly low. This is supported by studies in lactating animals, in which low drug concentrations were measured in milk. There are no data available for human breast milk.

Effects on Ability to Drive and Use Machines
There have been no specific studies of the effect of SERETIDE on the above activities, but the pharmacology of both drugs does not indicate any effect.
Adverse Reactions
As SERETIDE contains salmeterol and fluticasone propionate, the type and severity of adverse reactions associated with each of the compounds may be expected. There is no incidence of additional adverse events following concurrent administration of the two compounds.
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 and short-acting inhaled bronchodilator. Salmeterol/fluticasone propionate Evohaler should be discontinued immediately, the patient assessed and alternative therapy
instituted if necessary. Adverse events which have been associated with salmeterol or fluticasone propionate are given below.

Salmeterol:-
The pharmacological side effects of beta2-agonist treatment, such as tremor, subjective palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.
Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles) may occur, usually in susceptible patients.
There have been very rare reports of arthralgia.
Hypersensitivity reactions, including anaphylactic reactions such as oedema and angioedema, bronchospasm and anaphylactic shock have been reported very rarely.
There have also been uncommon reports of rash.
There have been reports of oropharyngeal irritation.
There have been common reports of muscle cramps.
There have been very rare reports of hyperglycaemia.

Fluticasone propionate:-
Hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients. There have been uncommon reports of cutaneous hypersensitivity reactions. There have also been rare reports of hypersensitivity reactions manifesting as angioedema (mainly facial and oropharyngeal oedema), respiratory symptoms (dyspnoea and/or
bronchospasm) and very rarely, anaphylactic reactions.
Both hoarseness and incidence of candidiasis may be relieved by gargling with water after use of salmeterol/fluticasone propionate Evohaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with salmeterol/fluticasone propionate Evohaler.
Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral
density, cataract and glaucoma (see Warnings and Precautions). There have been very rare reports of hyperglycaemia.
There have been very rare reports of anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children).

Salmeterol/fluticasone propionate clinical trials:-
The following undesirable effects were commonly reported:
Hoarseness/dysphonia, throat irritation, headache, candidiasis of mouth and throat and palpitations.

Salmeterol/fluticasone propionate postmarketing:-
There have been uncommon reports of cutaneous hypersensitivity reactions. There have also been rare reports of hypersensitivity reactions manifesting as angioedema (mainly facial and oropharyngeal oedema), respiratory symptoms (dyspnoea and/or bronchospasm) and very rarely, anaphylactic reactions.
There have been very rare reports of anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children).
There have also been very rare reports of hyperglycaemia.

Overdose
The available information on overdose with SERETIDE, salmeterol and/or fluticasone propionate is given below:
The expected symptoms and signs of salmeterol overdosage are those typical of excessive beta2–adrenergic stimulation, including tremor, headache, tachycardia,
increases in systolic blood pressure and hypokalaemia. The preferred antidotes are cardioselective beta-blocking agents, which should be used with caution in patients with
a history of bronchospasm. If SERETIDE therapy has to be withdrawn due to overdose of the beta agonist component of the drug, provision of appropriate replacement
corticosteroid therapy should be considered.
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 SERETIDE 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); observed features have included
hypoglycaemia associated with decreased consciousness and/or convulsions. 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.

It is not recommended that patients receive higher than approved doses of SERETIDE. It is important to review therapy regularly and titrate down to the lowest approved dose at which effective control of disease is maintained (see Dosage and Administration).

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics
SERETIDE clinical trials
Asthma
A large twelve-month study (Gaining Optimal Asthma ControL, GOAL) in 3416 asthma patients compared the efficacy and safety of SERETIDE versus inhaled corticosteroid
alone in achieving pre-defined levels of asthma control. Treatment was stepped-up every 12 weeks until ##‘Total controlEwas achieved or the highest dose of study drug was
reached. Control needed to be sustained for at least 7 out of the last 8 weeks of treatment.
The study showed that:
E71% of patients treated with SERETIDE achieved #‘Well-controlledEasthma compared with 59% of patients treated with inhaled corticosteroid alone.
E41% of patients treated with SERETIDE achieved ##‘Total controlEof asthma compared with 28% of patients treated with inhaled corticosteroid alone.
These effects were observed earlier with SERETIDE compared with inhaled corticosteroid alone and at a lower inhaled corticosteroid dose.

The GOAL study also showed that:
EThe rate of exacerbations was 29% lower with SERETIDE compared to inhaled corticosteroid treatment alone.
EAttaining ‘Well controlledEand ‘Totally controlledEasthma improved Quality of Life (QoL). 61% of patients reported minimal or no impairment on QoL, as measured by an asthma specific quality of life questionnaire, after treatment with SERETIDE compared to 8% at baseline.
#Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung function plus no night-time awakenings, no exacerbations and no side effects
enforcing a change in therapy.
##Total control of asthma; no symptoms, no SABA use greater than or equal to 80% predicted lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy.

Two further studies have shown improvements in lung function, percentage of symptom free days and reduction in rescue medication use, at 60% lower inhaled corticosteroid dose with SERETIDE compared to treatment with inhaled corticosteroid alone, whilst the control of the underlying airway inflammation, measured by bronchial biopsy and bronchoalveolar lavage, was maintained.

Additional studies have shown that treatment with SERETIDE significantly improves asthma symptoms, lung function and reduces the use of rescue medication compared to treatment with the individual components alone and placebo. Results from GOAL show that the improvements seen with SERETIDE, in these endpoints, are maintained over at least 12 months.

COPD
Symptomatic COPD patients without restriction to 10% reversibility to a short acting beta2-agonist:-
Placebo-controlled clinical trials, over 6 months, have shown that regular use of both SERETIDE 50/250 and 50/500 micrograms rapidly and significantly improves lung
function, significantly reduced breathlessness and the use of relief medication. There were also significant improvements in health status.
Symptomatic COPD patients who demonstrated less than 10% reversibility to a short acting beta2-agonist:-
Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of SERETIDE 50/500 micrograms rapidly and significantly improves lung function,
significantly reduced breathlessness and the use of relief medication. Over a 12-month period the risk of COPD exacerbations and the need for additional courses of oral
corticosteroids was significantly reduced. There were also significant improvements in health status.
SERETIDE 50/500 micrograms was effective in improving lung function and health status and reducing the risk of COPD exacerbations, in both current and ex-smokers.
Mechanism of action:-

SERETIDE contains salmeterol and fluticasone propionate which have differing modes of action. Salmeterol protects against symptoms, fluticasone propionate improves lung function and prevents exacerbations of the condition. SERETIDE can offer a more convenient regime for patients on concurrent beta-agonist and inhaled corticosteroid
therapy. The respective mechanisms of action of both drugs are discussed below:
Salmeterol:-
Salmeterol is a selective long-acting (12 hour) beta2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor.
These pharmacological properties of salmeterol offer more effective protection against histamine-induced bronchoconstriction and produce a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta2-agonists.
In vitro tests have shown salmeterol is a potent and long-lasting inhibitor of the release, from human lung, of mast cell mediators such as histamine, leukotrienes and
prostaglandin D2.
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 non-bronchodilator activity but the full clinical significance is not yet clear. This mechanism is different from the antiinflammatory effect of corticosteroids.

Fluticasone propionate:-
Fluticasone propionate given by inhalation at recommended doses has a potent glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms
and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
Daily output of adrenocortical hormones usually remain within the normal range during chronic treatment with inhaled fluticasone propionate, even at the highest recommended doses in children and adults. After transfer from other inhaled steroids, the daily output gradually improves despite past and present intermittent use of oral steroids, thus demonstrating return of normal adrenal function on inhaled fluticasone propionate. The adrenal reserve also remains normal during chronic treatment, as measured by a normal increment on a stimulation test. However, any residual impairment of adrenal reserve from previous treatment may persist for a considerable time and should be borne in mind (see Warnings and Precautions).

Pharmacokinetics
There is no evidence in animal or human subjects that the administration of salmeterol and fluticasone propionate 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 SERETIDE are very low, potential interactions with other substrates and inhibitors of CYP 3A4 cannot be excluded.
Salmeterol:-
Salmeterol acts locally in the lung therefore plasma levels are not an indication of therapeutic effects. In addition there are only limited data available on the
pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma due to the low plasma concentrations at therapeutic doses (approximately 200 picograms/ml or less) achieved after inhaled dosing. After regular dosing with salmeterol xinafoate, hydroxynaphthoic acid can be detected in the systemic circulation,
reaching steady state concentrations of approximately 100 nanograms/ml. These concentrations are up to 1000 fold lower than steady state levels observed in toxicity
studies. No detrimental effects have been seen following long-term regular dosing (more than 12 months) in patients with airway obstruction.

An in vitro study showed that salmeterol is extensively metabolised to E hydroxysalmeterol (aliphatic oxidation) by cytochrome P450 3A4 (CYP3A4). However, a repeat dose study with salmeterol and erythromycin in healthy volunteers showed no clinically significant changes in pharmacodynamic effects at 500 mg three times daily doses of erythromycin.

Fluticasone propionate:-
The absolute bioavailability of inhaled fluticasone propionate in healthy subjects varies between approximately 10 to 30% of the nominal dose depending on the inhalation
device used. In patients with ROAD or COPD a lesser degree of systemic exposure to inhaled fluticasone propionate has been observed. Systemic absorption occurs mainly
through the lungs and is initially rapid then prolonged. The remainder of the inhaled dose may be swallowed but contributes minimally to systemic exposure due to the low
aqueous solubility and pre-systemic metabolism, resulting in oral availability of less than 1%. There is a linear increase in systemic exposure with increasing inhaled dose. The disposition of fluticasone propionate is characterised by high plasma clearance (1150 ml/min), a large volume of distribution at steady-state (approximately 300 l) and a
terminal half-life of approximately 8 hours. Plasma protein binding is moderately high (91%). Fluticasone propionate is cleared very rapidly from the systemic circulation,
principally by metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4.
The renal clearance of fluticasone propionate is negligible (<0.2%) and less than 5% as the metabolite. Care should be taken when co-administering known CYP3A4 inhibitors, as there is potential for increased systemic exposure to fluticasone propionate.

Special Patient Populations
SERETIDE
Accuhaler/Diskus:
Population pharmacokinetic analysis was performed utilising data for asthmatic subjects (nine clinical studies for FP and five studies for salmeterol) and showed the following:
- Higher FP exposure seen following administration of SERETIDE (50/100 micrograms) compared to FP alone (100 micrograms) in adolescents and adults (ratio 1.52 [90% CI 1.08, 2.13]) and children (ratio 1.20 [90% CI 1.06, 1.37]).
- Higher FP exposure observed in children taking SERETIDE (50/100 micrograms) compared to adolescents and adults (ratio 1.63 [90% CI 1.35, 1.96]).
- The clinical relevance of these findings are not known, however, no differences in HPA axis effects were observed in clinical studies of up to 12 weeks duration
comparing SERETIDE (50/100 micrograms) and FP (100 micrograms) in both adolescents and adults and in children.
- FP exposure was similar at the higher SERETIDE 50/500 microgram dose compared to the equivalent FP dose alone.
- Higher salmeterol exposure was observed in children taking SERETIDE (50/100 micrograms) compared to adolescents and adults (ratio 1.23 [90% CI 1.10, 1.38]).
- The clinical relevance of these findings are not known, however there were no differences observed in cardiovascular effects or reports of tremor between adults,
adolescents and children in clinical studies of up to 12 weeks duration.

Pre-clinical Safety Data
Salmeterol xinafoate and fluticasone propionate 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 beta2-adrenoreceptor agonist and glucocorticosteroid.
In long term studies, salmeterol xinafoate induced benign tumours of smooth muscle in the mesovarium of rats and the uterus of mice.
Rodents are sensitive to the formation of these pharmacologically-induced tumours.
Salmeterol is not considered to represent a significant oncogenic hazard to man.
Co-administration of salmeterol and fluticasone propionate resulted in some cardiovascular interactions at high doses. In rats, mild atrial myocarditis and focal
coronary arteritis were transient effects that resolved with regular dosing. In dogs, heart rate increases were greater after co-administration than after salmeterol alone. No
clinically relevant serious adverse cardiac effects have been observed in studies in man. Co-administration did not modify other class-related toxicities in animals.
Extensive clinical experience with drugs in these classes has revealed no evidence that the effects are relevant at therapeutic doses. Neither salmeterol xinafoate or fluticasone propionate has shown any potential for genetic toxicity.
The non-CFC propellant, HFA134a, has been shown to have no toxic effect at very high vapour concentrations, far in excess of those likely to be experienced by patients, in a wide range of animal species exposed daily for periods of two years.

PHARMACEUTICAL PARTICULARS

List of Excipients
HFA 134a.

Incompatibilities
None reported.

Shelf Life
2 years.

Special Precautions for Storage
Replace the mouthpiece cover firmly and snap it into position.
SERETIDE Evohaler should not be stored above 30°C.
Protect from frost and direct sunlight.
As with most inhaled medications in pressurised canisters, the therapeutic effect of this medication may decrease when the canister is cold.
The canister should not be punctured, broken or burnt even when apparently empty.

Nature and Contents of Container
SERETIDE Evohaler comprises a suspension of salmeterol and fluticasone propionate in the non-CFC propellant HFA 134a. The suspension is contained in an aluminium alloy can sealed with a metering valve. The canisters are fitted into plastic actuators incorporating an atomising orifice and fitted with dustcaps. SERETIDE Evohaler has
been formulated in three strengths and one pack size, delivering 120 actuations per inhaler.

Instructions for Use/Handling
Testing your inhaler:-
Before using for the first time or if your inhaler has not been used for a week or more remove the mouthpiece cover by gently squeezing the sides of the cover, shake the
inhaler well, and release one puff into the air to make sure that it works.
Using your inhaler:-
1. Remove the mouthpiece cover by gently squeezing the sides of the cover.
2. Check inside and outside of the inhaler including the mouthpiece for the presence of loose objects.
3. Shake the inhaler well to ensure that any loose objects are removed and that the contents of the inhaler are evenly mixed.
4. Hold the inhaler upright between fingers and thumb with your thumb on the base,below the mouthpiece.
5. Breathe out as far as is comfortable and then place the mouthpiece in your mouth between your teeth and close your lips around it, but do not bite it.
6. Just after starting to breathe in through your mouth, press down on the top of the inhaler to release salmeterol and fluticasone propionate, while still breathing in
steadily and deeply.
7. While holding your breath, take the inhaler from your mouth and take your finger from the top of the inhaler. Continue holding your breath for as long as is comfortable.
8. To take the second puff keep the inhaler upright and wait about half a minute before repeating steps 3 to 7.
9. Replace the mouthpiece cover by firmly pushing and snapping the cap into position.

IMPORTANT:-
Do not rush stages 5, 6 and 7. It is important that you start to breathe in as slowly as possible just before operating your inhaler. Practise in front of a mirror for the first few
times. If you see "mist" coming from the top of your inhaler or the sides of your mouth you should start again from stage 2.
If your doctor has given you different instructions for using your inhaler, please follow them carefully. Tell your doctor if you have any difficulties.

Children:-
Young children may need help and an adult may need to operate the inhaler for them. Encourage the child to breathe out and operate the inhaler just after the child starts to
breathe in. Practice the technique together. Older children or people with weak hands should hold the inhaler with both hands. Put the two forefingers on top of the inhaler and both thumbs on the base below the mouthpiece.

Cleaning:-
Your inhaler should be cleaned at least once a week.
1. Remove the mouth piece cover.
2. Do not remove the canister from the plastic casing.
3. Wipe the inside and outside of the mouthpiece and the plastic casing with a dry cloth, tissue or cottonbud.
4. Replace the mouthpiece cover.

DO NOT PUT THE METAL CANISTER INTO WATER.
Not all presentations are available in every country.
Version number: GDS20/IPI08
Date of issue: 20 July 2006

SERETIDE EVOHALER is a trademark of the GlaxoSmithKline group of companies