4.1. Therapeutic indications

Sirdupla is indicated in the regular treatment of asthma where use of a combination product (long-acting β2 agonist and inhaled glucocorticosteroid) is appropriate:

- patients not adequately controlled with inhaled glucocorticosteroids and 'as needed' inhaled short-acting β2 agonist or

- patients already adequately controlled on both inhaled glucocorticosteroid and long-acting β2 agonist

4.2. Posology and method of administration

Sirdupla is indicated in adults 18 years of age and older only.

Sirdupla is not indicated for use in children, 12 years of age and younger or adolescents, 13 to 17 years of age.

Posology

Patients should be made aware that salmeterol/fluticasone propionate must be used daily for optimum benefit, even when asymptomatic.

Patients should be regularly reassessed by a doctor, so that the strength of salmeterol/fluticasone propionate 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. To Note: Sirdupla is only available in two strengths; it is not available in a lower strength product containing salmeterol 25 microgram and fluticasone propionate 50 microgram, a strength which is available for other similar fixed-dose combination products containing these two actives and currently available on the market. Therefore, when it is appropriate to titrate down to a dose of inhaled glucocorticosteroid below 125 micrograms, a change to an alternative fixed-dose combination of salmeterol and fluticasone propionate containing a lower dose of the inhaled glucocorticosteroid is required.

When long-term control of symptoms is maintained with the lowest strength of such an alternative fixed-dose combination given twice daily, then the next step could include a test of inhaled glucocorticosteroid alone. As an alternative, patients requiring a long-acting β2 agonist rather than treatment with an inhaled glucocorticosteroid alone, could be titrated to once daily use of this alternative lowest strength combination product 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 daytime symptoms the dose should be given in the morning.

Sirdupla should not be used for patients with mild asthma. Sirdupla could be considered for use in patients with moderate persistent asthma but only where control of symptoms cannot be maintained with a lower strength product containing a lower dose of the glucocorticosteroid

Patients should be given the strength of salmeterol/fluticasone propionate containing the appropriate fluticasone propionate dosage for the severity of their disease. If an individual patient should require dosages outside the recommended regimen, appropriate doses of β2 agonist and/or glucocorticosteroid should be prescribed.

Recommended doses:

Adults 18 years and older:

- Two inhalations of 25 micrograms salmeterol and 125 micrograms fluticasone propionate twice daily.

A short term trial of salmeterol/fluticasone propionate may be considered as initial maintenance therapy in adults 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. To Note: Sirdupla is not available in the lowest strength of this combination as currently available on the market and therefore an alternative fixed-dose combination of salmeterol and fluticasone propionate containing a lower dose of the inhaled glucocorticosteroid would need to be prescribed for the initial maintenance therapy in adults with moderate persistent asthma. The dose of the inhaled glucocorticosteroid may need to be increased to achieve control of asthma symptoms but once control is attained treatment should be reviewed and the dose of the inhaled glucocorticosteroid titrated downwards to the lowest dose at which effective control of symptoms is maintained. Consideration may be given as to whether patients should be stepped down to an inhaled glucocorticosteroid alone from the lowest strength combination product. 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 glucocorticosteroids remain the first line treatment for most patients. Sirdupla is not intended for the initial management of mild asthma. It is recommended to establish the appropriate dosage of inhaled glucocorticosteroid before any fixed-combination can be used in patients with severe asthma.

Paediatric population:

The safety and efficacy of Sirdupla in children, 12 years and younger and adolescents, 13-17 years of age have not been established. Sirdupla is not recommended for use in children and adolescents under 18 years of age (see section 5.1).

Use of an AeroChamber Plus® spacer device with Sirdupla is recommended in patients who have, or are likely to have, difficulties in coordinating actuation with inspiration. Only the AeroChamber Plus® spacer device should be used with Sirdupla. Other spacing devices should not be used with Sirdupla and patients should not switch from one spacer device to another.

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 use the recommended spacer device as switching to another spacer device can result in changes in the dose delivered to the lungs (see section 4.4).

Re-titration to the lowest effective dose should always be carried out when patients who have previously used an alternative product and spacer device are then transferred to Sirdupla with or without the AeroChamber Plus® 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 salmeterol/fluticasone propionate in patients with hepatic impairment.

Method of administration

For inhalation use.

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 the inhaler for the first time patients should test that it is working. Patients should remove the mouthpiece cover by gently squeezing the sides of the cover, hold the inhaler between the fingers and thumb with their thumb on the base, below the mouthpiece. To make sure that the inhaler works, the patient should shake it well, point the mouthpiece away from them and press the canister firmly to release a puff into the air. These steps should be repeated at least three times, shaking the inhaler before releasing each puff, until the counter reads 120.

If the inhaler has not been used for a week or more, or the inhaler gets very cold (below 0°C) the mouthpiece cover should be removed, the patient should shake the inhaler well and should 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 loose 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 mouthpiece.

6. Just after starting to breathe in through their mouth, patients should press firmly down on the top of the inhaler to release the medicine, 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 by firmly pushing and snapping the cap into position. This does not require excessive force, the cover should 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 3.

Patients should rinse their mouth out with water and spit out, and/or brush their teeth after each dose of medicine, in order to minimise the risk of oropharyngeal candidiasis and hoarseness.

Patients should consider getting a replacement when the counter shows the number 20. The counter will stop at 0 when all the recommended puffs have been used. Replace the inhaler when the counter reads 0.

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

Cleaning (also detailed in patient information leaflet):

Your inhaler should be cleaned at least once a week.

1. Remove the mouthpiece 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. This does not require excessive force, the cover should click into position.

DO NOT WASH OR PUT ANY PARTS OF THE INHALER IN WATER.

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Salmeterol/fluticasone propionate 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 inhaler to be used for relief in an acute asthma attack available at all times.

Patients should not be initiated on salmeterol/fluticasone propionate 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 salmeterol/fluticasone propionate. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Sirdupla.

Increased requirements for use of reliever medication (short-acting bronchodilators), or decreased response to reliever medication indicate 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 glucocorticosteroid therapy.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of salmeterol/fluticasone propionate. Regular review of patients as treatment is stepped down is important. The lowest effective dose of the combination of salmeterol and fluticasone propionate (which may mean a change to an alternative fixed-dose combination of salmeterol and fluticasone propionate containing a lower dose of the inhaled glucocorticosteroid) should be used (see section 4.2).

Treatment with salmeterol/fluticasone propionate should not be stopped abruptly due to risk of exacerbation. Therapy should be down-titrated under physician supervision.

As with all inhaled medication containing glucocorticosteroids, salmeterol/fluticasone propionate should be administered with caution in patients with active or quiescent pulmonary tuberculosis and fungal, viral or other infections of the airway. Appropriate treatment should be promptly instituted, if indicated.

Rarely, salmeterol/fluticasone propionate may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. Salmeterol/fluticasone propionate should be used with caution in patients with severe cardiovascular disorders or heart rhythm abnormalities and in patients with 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 (see section 4.8) 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 and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting bronchodilator and should be treated straightaway. Sirdupla should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

The pharmacological side effects of β2 agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.

Systemic effects may occur with any inhaled glucocorticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral glucocorticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children) (see Paediatric population sub-heading below for information on the systemic effects of inhaled glucocorticosteroids in children and adolescents). It is important, therefore, that the patient is reviewed regularly and the dose of inhaled glucocorticosteroid is reduced to the lowest dose at which effective control of asthma is maintained.

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Prolonged treatment of patients with high doses of inhaled glucocorticosteroids may result in adrenal suppression and acute adrenal crisis. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of fluticasone propionate between 500 and less than 1000 micrograms. 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 glucocorticosteroid 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 a fixed-dose combination of salmeterol and fluticasone propionate 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. Therefore these patients should be treated with special care and adrenocortical function regularly monitored. Patients who have required high dose emergency glucocorticosteroid 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 glucocorticosteroid 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 glucocorticosteroid side effects. There is also an increased risk of systemic side effects when combining fluticasone propionate with other potent CYP3A inhibitors (see section 4.5).

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 salmeterol and fluticasone propionate as a fixed-dose combination administered via the Diskus®/Accuhaler® compared with placebo (see section 4.8). In a 3-year COPD study, older patients, patients with a lower body mass index (<25 kg/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 Sirdupla should be re-evaluated. The safety and efficacy of Sirdupla has not been established in patients with COPD and therefore Sirdupla is not indicated for use in the treatment of patients with COPD.

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 (see section 4.5).

Paediatric population

Children and adolescents <16 years taking high doses of fluticasone propionate (typically 1000 micrograms/day) may be at particular risk. Systemic effects may occur, particularly at high doses prescribed for long periods. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, acute adrenal crisis and growth retardation in children and adolescents and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression. Consideration should be given to referring the child or adolescent to a paediatric respiratory specialist.

It is recommended that the height of children receiving prolonged treatment with inhaled glucocorticosteroid is regularly monitored. The dose of inhaled glucocorticosteroid should be reduced to the lowest dose at which effective control of asthma is maintained. To Note: Sirdupla is only available in two strengths; it is not available in a lower strength product containing salmeterol 25 microgram and fluticasone propionate 50 microgram, the strength which would be prescribed for use in children. Furthermore the safety and efficacy of Sirdupla in children, 12 years and younger and adolescents, 13-17 years of age have not been established. No data are available. Sirdupla is not recommended for use in children and adolescents under 18 years of age at this time (see section 4.2).

Sirdupla contains ethanol.

This medicinal product contains 0.73 mg of alcohol per inhalation which is equivalent to 12 mg/ml; the small amount in this medicinal product will not have any noticeable effect.

4.5. Interaction with other medicinal products and other forms of interaction

β adrenergic blockers may weaken or antagonise the effect of salmeterol. Both non-selective and selective β blockers should be avoided in patients with asthma, unless there are compelling reasons for their use. Potentially serious hypokalaemia may result from β2 agonist therapy. Particular caution is advised in acute severe asthma as this effect may be potentiated by concomitant treatment with xanthine derivatives, steroids and diuretics.

Concomitant use of other β 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 twice daily 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, cobicistat-containing products and moderate CYP3A inhibitors, such as erythromycin, is also expected to increase the systemic fluticasone propionate exposure and the risk of systemic side-effects.

Combination should be avoided unless the benefit outweighs the potential increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects

Salmeterol

Potent CYP3A4 inhibitors

Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 micrograms 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 (see section 4.4).

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 CYP3A4 inhibitors

Co-administration of erythromycin (500 mg orally three times a day) and salmeterol (50 micrograms 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

A large amount of data on pregnant women (more than 1000 pregnancy outcomes) indicates no malformative or foeto/neonatal toxicity of related to salmeterol and fluticasone propionate. Animal studies have shown reproductive toxicity after administration of β2 adrenoreceptor agonists and glucocorticosteroids (see section 5.3).

Administration of Sirdupla to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.

The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women.

Breast-feeding

It is unknown whether salmeterol and fluticasone propionate/metabolites are excreted in human milk.

Studies have shown that salmeterol and fluticasone propionate, and their metabolites, are excreted into the milk of lactating rats.

A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue Sirdupla therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

There are no data in humans. However, animal studies showed no effects of salmeterol or fluticasone propionate on fertility.

4.7. Effects on ability to drive and use machines

Sirdupla has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

As Sirdupla 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.

Adverse events which have been associated with salmeterol/fluticasone propionate are given below, listed by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and not known (cannot be estimated from the available data). Frequencies were derived from clinical trial data. The incidence in placebo was not taken into account.

System Organ Class

Adverse Event

Frequency

Infections and infestations

Candidiasis of the mouth and throat

Common

Pneumonia

Common1,3

Bronchitis

Common1,3

Oesophageal candidiasis

Rare

Immune system disorders

Hypersensitivity reactions with the following manifestations:

Cutaneous hypersensitivity reactions

Uncommon

Angioedema (mainly facial and oropharyngeal oedema)

Rare

Respiratory symptoms (dyspnoea)

Uncommon

Respiratory symptoms (bronchospasm)

Rare

Anaphylactic reactions including anaphylactic shock

Rare

Endocrine disorders

Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density

Rare4

Metabolism and nutrition disorders

Hypokalaemia

Common3

Hyperglycaemia

Uncommon4

Psychiatric disorders

Anxiety

Uncommon

Sleep disorders

Uncommon

Behavioural changes, including psychomotor hyperactivity and irritability (predominantly in children)

Rare

Depression, aggression (predominantly in children)

Not known

Nervous system disorders

Headache

Very common1

Tremor

Uncommon

Eye disorders

Cataract

Uncommon

Glaucoma

Rare4

Blurred vision (see section 4.4)

Not known

Cardiac disorders

Palpitations

Uncommon

Tachycardia

Uncommon

Cardiac arrhythmias (including, supraventricular tachycardia and extrasystoles).

Rare

Atrial fibrillation

Uncommon

Angina pectoris

Uncommon

Respiratory, thoracic and mediastinal disorders

Nasopharyngitis

Very Common2,3

Throat irritation

Common

Hoarseness/dysphonia

Common

Sinusitis

Common1,3

Paradoxical bronchospasm

Rare4

Skin and subcutaneous tissue disorders

Contusions

Common1,3

Musculoskeletal and connective tissue disorders

Muscle cramps

Common

Traumatic fractures

Common1,3

Arthralgia

Common

Myalgia

Common

1. Reported commonly in placebo

2. Reported very commonly in placebo

3. Reported over 3 years in a COPD study

4. See section 4.4

Description of selected adverse reactions

The pharmacological side effects of β2 agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting bronchodilator and should be treated straightaway. Sirdupla should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and throat and, rarely, of the oesophagus can occur in some patients. Both hoarseness and incidence of mouth and throat candidiasis may be relieved by rinsing the mouth with water and/or brushing the teeth after using the product. Symptomatic mouth and throat candidiasis can be treated with topical anti-fungal therapy whilst still continuing with Sirdupla.

Paediatric population

Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression and growth retardation in children and adolescents (see section 4.4). Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There are no data available from clinical trials on overdose with salmeterol/fluticasone propionate, however data on overdose with both drugs are given below:

Salmeterol

The signs and symptoms of salmeterol overdose are dizziness, increases in systolic blood pressure, tremor, headache and tachycardia. If Sirdupla therapy has to be withdrawn due to overdose of the β agonist component of the drug, provision of appropriate replacement steroid therapy should be considered. Additionally, hypokalaemia can occur and therefore serum potassium levels should be monitored. Potassium replacement should be considered.

Fluticasone propionate

Acute: Acute inhalation of fluticasone propionate doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not need emergency action as adrenal function is recovered in a few days, as verified by plasma cortisol measurements.

Chronic overdose of inhaled fluticasone propionate: Adrenal reserve should be monitored and treatment with a systemic glucocorticosteroid may be necessary. When stabilised, treatment should be continued with an inhaled glucocorticosteroid at the recommended dose (see section 4.4).

In cases of both acute and chronic fluticasone propionate overdose, Sirdupla therapy should be continued at a suitable dosage for symptom control.