25 micrograms of salmeterol (as salmeterol xinafoate) and 50, 125 or 250 micrograms of fluticasone propionate (delivered from the valve). This is equivalent to 21 micrograms of salmeterol and 44, 110 or 220 micrograms of fluticasone propionate delivered from the actuator (delivered dose).

Pressurised inhalation, suspension. The canister contains a white to off white suspension.

Seretide is indicated in the regular treatment of asthma where use of a combination product (long-acting beta-2-agonist and inhaled corticosteroid) is appropriate: -patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled short acting beta-2-agonist or -patients already adequately controlled on both inhaled corticosteroid and long-acting beta-2-agonist.

Seretide Evohaler is for inhalation use only.

Patients should be made aware that Seretide Evohaler must be used daily 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. 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 the lowest strength of the combination given twice daily then the next step could include a test of inhaled corticosteroid alone. As an alternative, patients requiring a long acting beta-2-agonist could be titrated to Seretide given once daily if, in the opinion of the prescriber, it would be adequate to maintain disease control. In the event of once daily dosing when the patient has a history of nocturnal symptoms the dose should be given at night and when the patient has a history of mainly day-time symptoms the dose should be given in the morning.

Patients should be given the strength of Seretide containing the appropriate fluticasone propionate dosage for the severity of their disease. Note: Seretide 25 microgram /50 microgram strength is not appropriate in adults and children with severe asthma. Prescribers should be aware that, in patients with asthma, fluticasone propionate is as effective as other inhaled steroids at approximately half the microgram daily dose. For example, 100mcg of fluticasone propionate is approximately equivalent to 200mcg of beclomethasone dipropionate (CFC containing) or budesonide. If an individual patient should require dosages outside the recommended regimen, appropriate doses of beta-agonist and/or corticosteroid should be prescribed.

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.

A short term trial of Seretide may be considered as initial maintenance therapy in adults or adolescents with moderate persistent asthma (defined as patients with daily symptoms, daily rescue use and moderate to severe airflow limitation) for whom rapid control of asthma is essential. In these cases, the recommended initial dose is two inhalations of 25 micrograms salmeterol and 50 micrograms fluticasone propionate twice daily. Once control of asthma is attained treatment should be reviewed and consideration given as to whether patients should be stepped down to an inhaled corticosteroid alone. Regular review of patients as treatment is stepped down is important.

A clear benefit has not been shown as compared to inhaled fluticasone propionate alone used as initial maintenance therapy when one or two of the criteria of severity are missing. In general inhaled corticosteroids remain the first line treatment for most patients. Seretide is not intended for the initial management of mild asthma. Seretide 25 microgram /50 micrograms strength is not appropriate in adults and children with severe asthma; it is recommended to establish the appropriate dosage of inhaled corticosteroid before any fixed combination can be used in patients with severe asthma.

Children 4 years and older:

Two inhalations of 25 micrograms salmeterol and 50 micrograms fluticasone propionate twice daily.

The maximum licensed dose of fluticasone propionate delivered by Seretide inhaler in children is 100mcg twice daily.

There are no data available for use of Seretide inhaler in children aged under 4 years.

Use of a spacer device with Seretide inhaler is recommended in patients who find it difficult to synchronise aerosol actuation with inspiration of breath. Either the Volumatic or AeroChamber Plus spacer device can be used (depending on National Guidance). Limited data are available that demonstrate an increase in systemic exposure when the AeroChamber Plus spacer device is used compared with the Volumatic spacer device.

Patients should be instructed in the proper use and care of their inhaler and spacer and their technique checked to ensure optimum delivery of the inhaled drug to the lungs. Patients should continue to use the same make of spacer device as switching between spacer devices can result in changes in the dose delivered to the lungs.

Re-titration to the lowest effective dose should always follow the introduction or change of a spacer device.

Special patient groups:

There is no need to adjust the dose in elderly patients or in those with renal impairment. There are no data available for use of Seretide in patients with hepatic impairment.

Instructions for Use:

Patients should be instructed in the proper use of their inhaler (see patient information leaflet)

During inhalation, the patient should preferably sit or stand. The inhaler has been designed for use in a vertical position.

Testing the inhaler:

Before using for the first time patients should remove the mouthpiece cover by gently squeezing the sides of the cover, shake the inhaler well, hold the inhaler between the fingers and thumb with your thumb at the base, below the mouthpiece and release puffs into the air until the counter reads 120 to make sure that it works. The inhaler should be shaken immediately before releasing each puff. If the inhaler has not been used for a week or more remove the mouthpiece cover, the patients should shake the inhaler well and release two puffs into the air. Each time the inhaler is activated the number on the counter will count down by one.

Use of the inhaler:

1. Patients should remove the mouthpiece cover by gently squeezing the sides of the cover.

2. Patients should check inside and outside of the inhaler including the mouthpiece for the presence of loose objects.

3. Patients should shake the inhaler well to ensure that any lose objects are removed and that the contents of the inhaler are evenly mixed

4. Patients should hold the inhaler upright between fingers and thumb with their thumb on the base, below the mouthpiece.

5. Patients should breathe out as far as is comfortable and then place the mouthpiece in their mouth between their teeth and close their lips around it, Patients should be instructed not to bite the mouth piece.

6. Just after starting to breathe in through their mouth, patients should press firmly down on the top of the inhaler to release Seretide, while still breathing in steadily and deeply.

7. While holding their breath, patients should take the inhaler from their mouth and take their finger from the top of the inhaler. Patients should continue holding their breath for as long as is comfortable.

8. To take a second inhalation, patients should keep the inhaler upright and wait about half a minute before repeating steps 3 to 7.

9. Patients should immediately replace the mouthpiece cover in the correct orientation by firmly pushing and snapping the cap into position. The cover does not require excessive force and it will click into position

IMPORTANT

Patients should not rush stages 5, 6 and 7. It is important that patients start to breathe in as slowly as possible just before operating their inhaler. Patients should practise in front of a mirror for the first few times. If they see "mist" coming from the top of their inhaler or the sides of their mouth they should start again from stage 2.

Patients should consider getting a replacement when the counter shows the number 020. The counter will stop at 000 when all the recommended puffs have been used. Replace the inhaler when the counter reads 000.

Patients should never try to alter the numbers on the counter or detach the counter from the metal canister. The counter cannot be reset and is permanently attached to the canister.

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 or tissue.

4. Replace the mouthpiece cover in the correct orientation. The cover does not require excessive force and it will click into position.

DO NOT PUT THE METAL CONTAINER IN WATER

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

Seretide Evohaler should not be used to treat acute asthma symptoms for which a fast and short acting bronchodilator is required. Patients should be advised to have their medicinal product to be used for relief in an acute asthma attack available at all times.

Patients should not be initiated on Seretide during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Serious asthma-related adverse events and exacerbations may occur during treatment with Seretide. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Seretide.

Increasing use of short-acting bronchodilators to relieve asthma symptoms indicates deterioration of asthma 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 undergo urgent medical assessment. Consideration should be given to increasing corticosteroid therapy. The patient should also be medically reviewed where the current dosage of Seretide has failed to give adequate control of asthma. Consideration should be given to additional corticosteroid therapies.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Seretide. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Seretide should be used.

Treatment with Seretide should not be stopped abruptly.

As with all inhaled medication containing corticosteroids, Seretide should be administered with caution in patients with pulmonary tuberculosis.

Rarely, Seretide may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. Therefore Seretide should be used with caution in patients with severe cardiovascular disorders, heart rhythm abnormalities, diabetes mellitus,thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium.

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

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. Seretide Evohaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Care should be taken when transferring patients to Seretide therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy.

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. 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, that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained.

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored.

Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children and adolescents <16years taking high doses of fluticasone (typically 1000mcg/day) may be at particular risk. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of fluticasone propionate between 500 and less than 1000mcg. Situations, which could potentially trigger acute adrenal crisis, include trauma, surgery, infection or any rapid reduction in dosage. Presenting symptoms are typically vague and may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, hypotension, decreased level of consciousness, hypoglycaemia, and seizures. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Systemic absorption of salmeterol and fluticasone propionate is largely through the lungs. As the use of a spacer device with a metered dose inhaler may increase drug delivery to the lungs it should be noted that this could potentially lead to an increase in the risk of systemic adverse effects. Single dose pharmacokinetic data have demonstrated that the systemic exposure to salmeterol and fluticasone propionate may be increased as much as two-fold when the AeroChamber Plus spacer device is used with Seretide inhaler as compared with the Volumatic spacer device.

The benefits of inhaled fluticasone propionate therapy should minimise the need for oral steroids, but patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time. Patients who have required high dose emergency corticosteroid therapy in the past may also be at risk. This possibility of residual impairment should always be borne in mind in emergency and elective situations likely to produce stress, and appropriate corticosteroid treatment must be considered. The extent of the adrenal impairment may require specialist advice before elective procedures.

Ritonavir can greatly increase the concentration of fluticasone propionate in plasma. Therefore, concomitant use should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects. There is also an increased risk of systemic side effects when combining fluticasone propionate with other potent CYP3A inhibitors.

There was an increased reporting of lower respiratory tract infections (particularly pneumonia and bronchitis) in a 3 year study in patients with Chronic Obstructive Pulmonary Disease (COPD) receiving Seretide compared with placebo. In a 3 year COPD study, older patients, patients with a lower body mass index (<25kg/m²) and patients with very severe disease (FEV₁<30% predicted) were at greatest risk of developing pneumonia regardless of treatment. Physicians should remain vigilant for the possible development of pneumonia and other lower respiratory tract infections in patients with COPD as the clinical features of such infections and exacerbation frequently overlap. If a patient with severe COPD has experienced pneumonia the treatment with Seretide should be re-evaluated.

Data from a large clinical trial (the Salmeterol Multi-Center Asthma Research Trial, SMART) suggested African-American patients were at increased risk of serious respiratory-related events or deaths when using salmeterol compared with placebo. It is not known if this was due to pharmacogenetic or other factors. Patients of black African or Afro-Caribbean ancestry should therefore be asked to continue treatment but to seek medical advice if asthma symptoms remained uncontrolled or worsen whilst using Seretide.

Concomitant use of systemic ketoconazole significantly increases systemic exposure to salmeterol. This may lead to an increase in the incidence of systemic effects (e.g. prolongation in the QTc interval and palpitations). Concomitant treatment with ketoconazole or other potent CYP3A4 inhibitors should therefore be avoided unless the benefits outweigh the potentially increased risk of systemic side effects of salmeterol treatment.

Both non-selective and selective beta-blockers should be avoided in patients with asthma, unless there are compelling reasons for their use.

Concomitant use of other beta-adrenergic containing drugs can have a potentially additive effect.

Fluticasone Propionate

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.

In an interaction study in healthy subjects with intranasal fluticasone propionate, ritonavir (a highly potent cytochrome P450 3A4 inhibitor) 100 mg b.i.d. increased the fluticasone propionate plasma concentrations several hundred fold, resulting in markedly reduced serum cortisol concentrations. Information about this interaction is lacking for inhaled fluticasone propionate, but a marked increase in fluticasone propionate plasma levels is expected. Cases of Cushing's syndrome and adrenal suppression have been reported. The combination should be avoided unless the benefit outweighs the increased risk of systemic glucocorticoid side-effects.

In a small study in healthy volunteers, the slightly less potent CYP3A inhibitor ketoconazole increased the exposure of fluticasone propionate after a single inhalation by 150%. This resulted in a greater reduction of plasma cortisol as compared with fluticasone propionate alone. Co-treatment with other potent CYP3A inhibitors, such as itraconazole, is also expected to increase the systemic fluticasone propionate exposure and the risk of systemic side-effects. Caution is recommended and long-term treatment with such drugs should if possible be avoided.

Salmeterol

Potent CYP3A4 inhibitors

Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 mcg inhaled twice daily) in 15 healthy subjects for 7 days resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC). This may lead to an increase in the incidence of other systemic effects of salmeterol treatment (e.g. prolongation of QTc interval and palpitations) compared with salmeterol or ketoconazole treatment alone.

Clinically significant effects were not seen on blood pressure, heart rate, blood glucose and blood potassium levels. Co-administration with ketoconazole did not increase the elimination half-life of salmeterol or increase salmeterol accumulation with repeat dosing.

The concomitant administration of ketoconazole should be avoided, unless the benefits outweigh the potentially increased risk of systemic side effects of salmeterol treatment. There is likely to be a similar risk of interaction with other potent CYP3A4 inhibitors (e.g. itraconazole, telithromycin, ritonavir).

Moderate CYP 3A4 inhibitors

Co-administration of erythromycin (500mg orally three times a day) and salmeterol (50mcg inhaled twice daily) in 15 healthy subjects for 6 days resulted in a small but non-statistically significant increase in salmeterol exposure (1.4-fold Cmax and 1.2-fold AUC). Co-administration with erythromycin was not associated with any serious adverse effects.

Allen & Hanburys Ltd

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