AirFluSal Forspiro is indicated for use in adults 18 years of age and older only.

Asthma

AirFluSal Forspiro is indicated in the regular treatment of adults with severe asthma where use of a combination product (long-acting β ₂ agonist [LABA] and inhaled corticosteroid [ICS]) is appropriate:

Patients not adequately controlled on a lower strength corticosteroid combination product

or

Patients already controlled on a high dose inhaled corticosteroid and long-acting β ₂ agonist.

Chronic Obstructive Pulmonary Disease (COPD)

AirFluSal Forspiro is indicated for the symptomatic treatment of adults with COPD, with a forced expiratory volume in one second (FEV₁) <60% predicted normal (pre-bronchodilator) and a history of repeated exacerbations and who have significant symptoms despite regular bronchodilator therapy.

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

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

Route of administration: Inhalation use

Patients should be made aware that AirFluSal Forspiro must be used regularly, every day for optimum benefit, even when asymptomatic.

Patients should be regularly reassessed by a doctor, so that the strength of the salmeterol/fluticasone propionate inhaler they are receiving remains optimal and is only changed on medical advice.

In patients with asthma, the dose should always be titrated to the lowest dose at which effective control of symptoms is maintained.

To Note: AirFluSal Forspiro is available on the market in the strength of 50 micrograms of salmeterol and 500 micrograms of fluticasone propionate per metered dose only; AirFluSal Forspiro is not available in any strengths lower than 50 micrograms of salmeterol and 500 micrograms of fluticasone propionate per metered dose. Therefore, when it is appropriate to titrate down to a lower strength not available for AirFluSal Forspiro, a change to an alternative fixed dose combination of salmeterol and fluticasone propionate containing a lower dose of the inhaled corticosteroid is required.

Patients should be given a strength of salmeterol/fluticasone propionate inhaler containing the appropriate fluticasone propionate dosage for the severity of their disease. AirFluSal Forspiro is only appropriate for use in the treatment of patients with severe asthma. If an individual patient should require dosages outside the recommended regimen, appropriate doses of β ₂ agonist and/or corticosteroid should be prescribed.

Posology

Recommended doses:

Asthma

Adults – aged 18 years and older:

One inhalation of 50 micrograms salmeterol and 500 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 alternative fixed-dose combination of salmeterol and fluticasone propionate containing a lower dose of the inhaled corticosteroid and then ultimately to an inhaled corticosteroid alone. Regular review of patients as treatment is stepped down is important.

The lowest effective dose of the inhaled corticosteroid should be used.

A clear benefit has not been shown as compared with 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.

AirFluSal Forspiro is for the treatment of patients with severe asthma only. It should not be used for the treatment of patients with mild or moderate asthma or for the initiation of treatment for patients with severe asthma unless the requirement for such a high dose of the corticosteroid together with a long-acting β ₂ agonist has been established previously.

AirFluSal Forspiro is not intended as the treatment of asthma when a fixed-dose combination of salmeterol and fluticasone propionate is required for the first time. Patients should commence treatment with a fixed-dose combination containing a lower dose of the corticosteroid component and will then be titrated up in respect of the corticosteroid dose until control of asthma is achieved. Once control of asthma is achieved patients should be reviewed regularly and the dose of inhaled corticosteroid titrated downwards as appropriate to maintain disease control.

It is recommended to establish the appropriate dosage of inhaled corticosteroid before any fixed-dose combination can be used in patients with severe asthma.

COPD

Adults:

One inhalation of 50 micrograms salmeterol and 500 micrograms fluticasone propionate twice daily.

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 on the use of AirFluSal Forspiro in patients with hepatic impairment.

Paediatric population:

AirFluSal Forspiro is not recommended for use in either children aged 12 years and younger or in adolescents aged 13 to 17 years.

The safety and efficacy of AirFluSal Forspiro in children and adolescents aged less than 18 years of age has not been established. No data are available.

Instructions for use:

Patients should be demonstrated how to use the Forspiro inhaler and correct use should be checked regularly.

The inhaler contains 60 doses of powder medication in a coiled strip of foil. It has a dose counter which indicates how many doses are left counting down from 60 to 0. When the last 10 doses have been reached the numbers will be on a red background.

The inhaler is not refillable - it should be disposed of when it is empty and be replaced with a new one.

Before using the inhaler

• The transparent side chamber door should be opened.

• The foil strip should be removed from the side chamber by carefully tearing away the full length of strip against the 'teeth' of the side chamber as shown below. The strip should not be pulled or tugged.

• The side chamber door should be closed and the used strip should be disposed of.

Note: As the inhaler is used the side chamber will gradually fill up with used strip. The foil strips with black bars don't contain medication. Eventually the numbered sections of the strip will appear in the side chamber. There should never be more than 2 sections of foil strip in the side chamber as they may cause the inhaler to jam. The strip should be torn away carefully as shown above, and disposed of safely.

Using the inhaler

The inhaler should be held in hands, as seen in the pictures.

1. Open

• The protective cap should be opened downwards to reveal the mouthpiece.

• The dose counter should be checked to see how many doses are left.

2. Preparation of the dose

• The edge of the white lever should be lifted up. The side chamber should be closed.

Note: The white lever should only be operated when the patient is ready to inhale a dose of the medication. If the patient plays with the white lever he/she will waste doses.

• Open: The white lever should be moved over fully as far as it will go and until it clicks. This action moves a new dose into position with the number at the top.

• Close: Afterwards the white lever should be closed fully so that it clicks back into its original position. The inhaler is now ready for immediate use.

3. Inhalation of the dose

• Away from the inhaler mouthpiece, the patient should breathe out as much as is comfortable. It should never be breathed directly into the inhaler as this could affect the dose.

• The inhaler should be held level with the protective cap pointing downwards.

• The lips should be closed firmly around the mouthpiece.

• The patient should breathe in steadily and deeply through the inhaler, not through the nose.

• The inhaler should be removed from the mouth and the breath should be held for 5-10 seconds or as long as is possible without causing discomfort.

• Afterwards, the patient should breathe out slowly, but not into the inhaler.

• The protective cap should be closed over the mouthpiece.

• The mouth should be rinsed with water, which should be spat out afterwards. This may help to prevent getting fungal infections in the mouth and becoming hoarse.

Cleaning

• The outside of the mouthpiece should be wiped with a clean, dry tissue if necessary.

• The inhaler should not be taken apart to clean it or for any other purpose.

• The inhaler parts must not be cleaned with water or wet wipes as dampness can affect the dose.

• Pins or other sharp objects must never be inserted into the mouthpiece, or any other part, as this may damage the inhaler.

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

Asthma

AirFluSal Forspiro is for use in patients with severe asthma only.

AirFluSal Forspiro should not be used in patients with mild or mild to moderate asthma.

AirFluSal Forspiro should not be used as initial maintenance therapy in patients with moderate persistent asthma.

AirFluSal Forspiro should not be used for the initiation of treatment for patients with severe asthma unless the requirement for such a high dose of the corticosteroid together with a long-acting β ₂ agonist has been established previously.

AirFluSal Forspiro should not be used in children and adolescents less than 18 years of age with asthma.

AirFluSal Forspiro 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 AirFluSal Forspiro 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 AirFluSal Forspiro. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on AirFluSal Forspiro.

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 corticosteroid therapy.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of the inhaled corticosteroid. As AirFluSal Forspiro is available in the strength of 50 micrograms of salmeterol and 500 micrograms of fluticasone propionate per metered dose only, a change to an alternative fixed dose combination product of salmeterol and fluticasone propionate containing a lower dose of the inhaled corticosteroid is required when it is appropriate to titrate down to a lower dose of the inhaled corticosteroid.

Regular review of patients as treatment is stepped down is important. The lowest effective dose of the inhaled corticosteroid should be used (see Section 4.2).

COPD

For patients with COPD experiencing exacerbations, treatment with systemic corticosteroids is typically indicated, therefore patients should be instructed to seek medical attention if symptoms deteriorate with AirFluSal Forspiro.

Cessation of therapy

Treatment with AirFluSal Forspiro should not be stopped abruptly in patients with asthma due to risk of exacerbation. Therapy should be down-titrated under physician supervision (see above).

For patients with COPD cessation of therapy may also be associated with symptomatic decompensation and should be supervised by a physician.

Caution with special diseases

As with all inhaled medication containing corticosteroids, AirFluSal Forspiro 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, AirFluSal Forspiro may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. AirFluSal Forspiro 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.

Paradoxical bronchospasm

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. AirFluSal Forspiro should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Beta 2 adrenoreceptor agonists

The pharmacological side effects of β ₂ agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.

Systemic effects

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, 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 paragraphs under the sub-heading Paediatric Population, below). 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.

Adrenal function

Prolonged treatment of patients with high doses of inhaled corticosteroids 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 corticosteroid cover should be considered during periods of stress or elective surgery.

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 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.

Interactions with other medicinal products

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 in which case patients should be monitored for systemic corticosteroid side-effects. There is also an increased risk of systemic side effects when combining fluticasone propionate with other potent CYP3A inhibitors, including cobicistat-containing products (see section 4.5).

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).

Respiratory tract infections

There was an increased reporting of lower respiratory tract infections (particularly pneumonia and bronchitis) in the TORCH study in patients with COPD receiving salmeterol/fluticasone propionate 50/500 micrograms twice daily compared with placebo as well as in studies SCO40043 and SCO100250 comparing a lower dose of salmeterol/fluticasone propionate 50/250 micrograms twice daily, (a dose not authorised for use in COPD) with salmeterol 50 micrograms twice daily only (see section 4.8 and section 5.1). A similar incidence of pneumonia in the salmeterol/fluticasone propionate group was seen across all studies. In TORCH, 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, treatment with AirFluSal Forspiro should be re-evaluated.

Pneumonia in patients with COPD

An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.

There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. If a patient with severe COPD has experienced pneumonia, treatment with AirFluSal Forspiro should be re-evaluated.

Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.

Visual disturbance

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.

Ethnic populations

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 (see section 5.1). 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 symptoms remain uncontrolled or worsen whilst using AirFluSal Forspiro.

Paediatric Population

AirFluSal Forspiro is not indicated for use in children and adolescents under the age of 18 years (see Section 4.2). However, it should be noted that children and adolescents less than 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 corticosteroids is regularly monitored. The dose of inhaled corticosteroid should always be reduced to the lowest dose at which effective control of asthma is maintained.

To Note: AirFluSal Forspiro is only available in one high strength, it is not available as either a low strength product containing salmeterol 50 microgram and fluticasone propionate 100 microgram, or a mid-strength product containing salmeterol 50 microgram and fluticasone propionate 250 microgram. The maximum authorised dose of fluticasone propionate formulated as an inhalation powder for use in children is 100 microgram twice daily – as is available in the low strength product – and therefore this high strength product would not be appropriate, in any event, for use in children 12 years of age and younger.

Furthermore the safety and efficacy of AirFluSal Forspiro in children, 12 years of age and younger and adolescents, 13-17 years of age have not been established. No data are available.

Therefore AirFluSal Forspiro is not recommended for use in children and adolescents under 18 years of age at this time (see Section 4.2).

Oral infections

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 the incidence of candidiasis of the mouth and throat may be relieved by rinsing the mouth with water and spitting the water out and/or brushing the teeth after using the product. Symptomatic candidiasis of the mouth and throat can be treated with topical anti-fungal therapy whilst still continuing with AirFluSal Forspiro.

Excipients

AirFluSal Forspiro contains 11.95 mg lactose/dose. This amount does not normally cause problems in lactose intolerant people. However lactose may contain small amounts of milk proteins which may cause allergic reactions in those with severe hypersensitivity or allergy to milk protein.

Beta adrenergic blockers may weaken or antagonise the effect of salmeterol. Both non-selective and selective β blockers should be avoided unless there are compelling reasons for their use.

Potentially serious hypokalaemia may result from β ₂ 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 medicinal products 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 and 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. The combination should be avoided unless the benefit outweighs the 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 CYP 3A4 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.

Pregnancy

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicates no malformative or feto/neonatal toxicity of salmeterol and fluticasone propionate. Animal studies have shown reproductive toxicity after administration of β ₂ -adrenoreceptor agonists and glucocorticosteroids (see section 5.3).

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

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 breast-feeding or to discontinue AirFluSal Forspiro therapy taking into account the benefit of breast-feeding 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.

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

As AirFluSal Forspiro 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); very rare (<1/10,000); 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.

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

5 See section 5.1.

Description of selected adverse reactions

The pharmacological side effects of β ₂ 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. AirFluSal Forspiro 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 the incidence of mouth and throat candidiasis may be relieved by rinsing the mouth with water and spitting the water out 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 a fixed-dose combination of salmeterol and fluticasone propionate.

Paediatric population

AirFluSal Forspiro is not indicated for use in children and adolescents under the age of 18 years (see Section 4.2). Possible systemic effects in these age groups 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 (www.mhra.gov.uk/yellowcard).

There are no data available from clinical trials on overdose with AirFluSal Forspiro; however data on overdose with both active substances are given below:

Salmeterol

The signs and symptoms of salmeterol overdose are dizziness, increases in systolic blood pressure, tremor, headache and tachycardia. If AirFluSal Forspiro therapy has to be withdrawn due to overdose of the β agonist component of the medicinal product, 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 overdose: 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: Adrenal reserve should be monitored and treatment with a systemic corticosteroid may be necessary. When stabilised, treatment should be continued with an inhaled corticosteroid at the recommended dose. See section 4.4: risk of adrenal suppression.

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

Pharmacotherapeutic group: Drugs for obstructive airway diseases; adrenergics in combination with corticosteroids or other drugs, excl. anticholinergics

ATC code: R03AK06

Mechanism of action:

AirFluSal Forspiro contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both active substances are discussed below:

Salmeterol:

Salmeterol is a selective long-acting (12 hour) β ₂ -adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor.

Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting β ₂ agonists (SABA).

Fluticasone propionate:

Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, with less adverse effects than when corticosteroids are administered systemically.

Clinical efficacy and safety:

The studies described below (GOAL, TORCH and SMART) were carried out with this same fixed-dose combination, salmeterol xinafoate and fluticasone propionate, but studied a previously authorised product; the studies described were not carried out with AirFluSal Forspiro.

Salmeterol/Fluticasone propionate – Asthma clinical trials

A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of salmeterol/fluticasone propionate versus inhaled corticosteroid (fluticasone propionate) alone to determine whether the goals of asthma management were achievable. Treatment was stepped up every 12 weeks until **total control was achieved or the highest dose of study drug was reached. GOAL showed more patients treated with salmeterol/fluticasone propionate achieved asthma control than patients treated with inhaled corticosteroid (ICS) alone and this control was attained at a lower corticosteroid dose.

*Well Controlled asthma was achieved more rapidly with salmeterol/fluticasone propionate than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual Well Controlled week was 16 days for salmeterol/fluticasone propionate compared with 37 days for the ICS group. In the subset of steroid naive asthmatics the time to an individual Well Controlled week was 16 days in the salmeterol/fluticasone propionate treatment compared with 23 days following treatment with ICS.

The overall study results showed:

*Well controlled asthma; less than or equal to 2 days with symptom score greater than 1 (symptom score 1 defined as 'symptoms for one short period during the day'), SABA use on less than or equal to 2 days and less than or equal to 4 occasions/week, greater than or equal to 80% predicted morning peak expiratory flow, 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 morning peak expiratory flow, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy

The results of this study suggest that salmeterol/fluticasone 50/100 microgram twice daily may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential.

A double-blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥ 18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of salmeterol/fluticasone propionate for two weeks. The study showed that doubling the inhalations of each strength of salmeterol/fluticasone propionate for up to 14 days resulted in a small increase in β agonist-related adverse events (tremor - 1 patient [1%] vs 0, palpitations - 6 [3%] vs 1 [<1%], muscle cramps - 6[3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid related adverse events (e.g. oral candidiasis - 6 [6%] vs 16 [8%], hoarseness - 2 [2%] vs 4 [2%]) compared with one inhalation twice daily. The small increase in β agonist-related adverse events should be taken into account if doubling the dose of salmeterol/fluticasone propionate is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy.

Salmeterol/fluticasone propionate – Chronic obstructive pulmonary disease (COPD) clinical trials

TORCH was a 3-year study to assess the effect of treatment with salmeterol/fluticasone propionate 50/500 microgram twice daily, salmeterol 50 micrograms twice daily, fluticasone propionate 500 micrograms twice daily or placebo on all-cause mortality in patients with COPD. COPD patients with a baseline (pre-bronchodilator) FEV₁ <60% of predicted normal were randomised to double-blind medication. During the study, patients were permitted usual COPD therapy with the exception of other inhaled corticosteroids, long-acting bronchodilators and long-term systemic corticosteroids. Survival status at 3 years was determined for all patients regardless of withdrawal from study medication. The primary endpoint was reduction in all-cause mortality at 3 years for salmeterol/fluticasone propionate vs placebo.

There was a trend towards improved survival in subjects treated with salmeterol/fluticasone propionate compared with placebo over 3 years however this did not achieve the statistical significance level p≤ 0.05.

The percentage of patients who died within 3 years due to COPD-related causes was 6.0% for placebo, 6.1% for salmeterol, 6.9% for fluticasone propionate and 4.7% for salmeterol/fluticasone propionate.

The mean number of moderate to severe exacerbations per year was significantly reduced with salmeterol/fluticasone propionate as compared with treatment with salmeterol, fluticasone propionate and placebo (mean rate in the salmeterol/fluticasone propionate group 0.85 compared with 0.97 in the salmeterol group, 0.93 in the fluticasone propionate group and 1.13 in the placebo group). This translates to a reduction in the rate of moderate to severe exacerbations of 25% (95% CI: 19% to 31%; p<0.001) compared with placebo, 12% compared with salmeterol (95% CI: 5% to 19%, p=0.002) and 9% compared with fluticasone propionate (95% CI: 1% to 16%, p=0.024). Salmeterol and fluticasone propionate significantly reduced exacerbation rates compared with placebo by 15% (95% CI: 7% to 22%; p<0.001) and 18% (95% CI: 11% to 24%; p<0.001) respectively.

Health Related Quality of Life, as measured by the St George's Respiratory Questionnaire (SGRQ) was improved by all active treatments in comparison with placebo. The average improvement over three years for salmeterol/fluticasone compared with placebo was -3.1 units (95% CI: -4.1 to -2.1; p<0.001), compared with salmeterol was -2.2 units (p<0.001) and compared with fluticasone propionate was -1.2 units (p=0.017). A 4-unit decrease is considered clinically relevant.

The estimated 3-year probability of having pneumonia reported as an adverse event was 12.3% for placebo, 13.3% for salmeterol, 18.3% for fluticasone propionate and 19.6% for salmeterol/fluticasone propionate (hazard ratio for salmeterol/fluticasone propionate vs placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001). There was no increase in pneumonia related deaths; deaths while on treatment that were adjudicated as primarily due to pneumonia were 7 for placebo, 9 for salmeterol, 13 for fluticasone propionate and 8 for salmeterol/fluticasone propionate. There was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% fluticasone propionate and 6.3% salmeterol/fluticasone propionate; hazard ratio for salmeterol/fluticasone propionate vs placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248.

Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of salmeterol/fluticasone propionate 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication.

Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of salmeterol/fluticasone propionate 50/250 micrograms twice daily (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms twice daily on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation.

The trials had a 4-week run-in period during which all subjects received open-label salmeterol/ fluticasone propionate 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ fluticasone propionate 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (β ₂ agonist and anticholinergic drugs), salbutamol/ipratropium bromide combination products, oral β ₂ agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies.

The results of both studies showed that treatment with salmeterol/fluticasone propionate 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured salmeterol/fluticasone propionate 50/250 micrograms twice daily over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the salmeterol/fluticasone propionate 50/250 micrograms twice daily group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the salmeterol/fluticasone propionate 50/250 micrograms twice daily group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with salmeterol/fluticasone propionate 50/250 micrograms twice daily appears to be of similar magnitude to the incidence reported following treatment with salmeterol/fluticasone propionate 50/500 micrograms twice daily in TORCH.

The Salmeterol Multi-center Asthma Research Trial (SMART)

SMART was a multi-centre, randomised, double blind, placebo-controlled, parallel group 28-week study in the US which randomised 13,176 patients to salmeterol (50 micrograms twice daily) and 13,179 patients to placebo in addition to the patients' usual asthma therapy. Patients were enrolled if ≥ 12 years of age, with asthma and if currently using asthma medication (but not a LABA). Baseline ICS use at study entry was recorded, but not required in the study. The primary endpoint in SMART was the combined number of respiratory-related deaths and respiratory-related life-threatening experiences.

Key findings from SMART: primary endpoint

(Risk in bold is statistically significant at the 95% level.)

Key findings from SMART by inhaled steroid use at baseline: secondary endpoints

(*=could not be calculated because of no events in placebo group. Risk in bold figures is statistically significant at the 95% level. The secondary endpoints in the table above reached statistical significance in the whole population.) The secondary endpoints of combined all cause death or life-threatening experience, all cause death, or all cause hospitalisation did not reach statistical significance in the whole population.

Paediatric population

AirFluSal Forspiro is not recommended for use in children and adolescents aged less than 18 years. The safety and efficacy of AirFluSal Forspiro in this young population have not been established. The data presented below refer to a lower dose of the fixed-dose combination containing these two actives, a dose and strength which is not available for AirFluSal Forspiro. The studies described were carried out with a previously authorised product available in three different strengths; the studies were not carried out with AirFluSal Forspiro.

In a study in 158 children aged 6 to 16 years with symptomatic asthma, the combination of fluticasone propionate/salmeterol is as efficacious as doubling the dose of fluticasone propionate in respect of symptom control and lung function. This study was not designed to investigate the effect on exacerbations.

In a 12-week trial of children aged 4 to 11 years [n=257] treated with either salmeterol/fluticasone propionate 50/100 or salmeterol 50 micrograms + fluticasone propionate 100 micrograms both twice daily, both treatment arms experienced a 14% increase in peak expiratory flow rate as well as improvements in symptom score and rescue salbutamol use. There were no differences between the two treatment arms. There were no differences in safety parameters between the two treatment arms.

In a 12-week trial of children 4 to 11 years of age [n=203] randomized in a parallel-group study with persistent asthma and who were symptomatic on inhaled corticosteroid, safety was the primary objective. Children received either salmeterol/fluticasone propionate (50/100 micrograms) or fluticasone propionate (100 micrograms) alone twice daily. Two children on fluticasone propionate/salmeterol and 5 children on fluticasone propionate withdrew because of worsening asthma. After 12 weeks no children in either treatment arm had abnormally low 24-hour urinary cortisol excretion. There were no other differences in safety profile between the treatment arms.

For pharmacokinetic purposes each component can be considered separately.

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 picogram/mL or less) achieved after inhaled dosing.

Fluticasone propionate:

Absorption:

The absolute bioavailability of a single dose of inhaled fluticasone propionate in healthy subjects varies between approximately 5-11% of the nominal dose depending on the inhalation device used. In patients with asthma 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.

Distribution:

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 91%.

Biotransformation:

Fluticasone propionate is cleared very rapidly from the systemic circulation. The main pathway is metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Other unidentified metabolites are also found in the faeces.

Elimination:

The renal clearance of fluticasone propionate is negligible. Less than 5% of the dose is excreted in urine, mainly as metabolites. The main part of the dose is excreted in faeces as metabolites and unchanged drug.

Paediatric population

AirFluSal Forspiro is not recommended for use in children and adolescents aged less than 18 years. The safety and efficacy of AirFluSal Forspiro in this young population have not been established. The data presented below refer to a lower dose of the fixed-dose combination containing these two actives, a dose and strength which is not available for AirFluSal Forspiro.

In a population pharmacokinetic analysis from 9 controlled clinical trials of 350 patients with asthma aged 4 to 77 years (174 patients 4 to 11 years of age) higher fluticasone propionate systemic exposure following treatment with salmeterol/fluticasone propionate inhalation powder 50/100 compared with fluticasone propionate inhalation powder 100 was seen.

The effect of 21 days of treatment with salmeterol/fluticasone propionate pressurised inhaler 25/50 microgram (2 inhalations twice daily with or without a spacer) or salmeterol/fluticasone propionate 50/100 microgram, inhalation powder (1 inhalation twice daily) was evaluated in 31 children aged 4 to 11 years with mild asthma.

Systemic exposure to fluticasone propionate was similar for salmeterol/fluticasone propionate pressurised inhaler with spacer (107 pg hr/mL [95% CI: 45.7, 252.2]) and salmeterol/fluticasone propionate, inhalation powder (138 pg hr/mL [95% CI: 69.3, 273.2]), but lower for salmeterol/fluticasone propionate pressurised inhaler without spacer (24 pg hr/mL [95% CI: 9.6, 60.2]). Systemic exposure to salmeterol was similar for salmeterol/fluticasone propionate pressurised inhaler without spacer, salmeterol/fluticasone propionate pressurised inhaler with spacer, and salmeterol/fluticasone propionate, inhalation powder (126 pg hr/mL [95% CI: 70, 225], 103 pg hr/mL [95% CI: 54, 200], and 110 pg hr/mL [95% CI: 55, 219], respectively).

The only safety concerns for human use derived from animal studies of salmeterol xinafoate and fluticasone propionate given separately were effects associated with exaggerated pharmacological actions.

In animal reproduction studies, glucocorticosteroids have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant for man given recommended doses. Animal studies with salmeterol xinafoate have shown embryofoetal toxicity only at high exposure levels. Following co-administration, increased incidences of transposed umbilical artery and incomplete ossification of occipital bone were found in rats at doses associated with known glucocorticoid-induced abnormalities.

Lactose monohydrate

Not applicable.

2 years

Do not store above 25 ° C.

The plastic materials of the inhaler are:

acrylonitrile butadiene styrene, methyl methacrylate acrylonitrile butadiene styrene, polyoxymethylene and polybutylene terapthalate.

Plastic inhalation device containing an OPA/Al/PVC-Al blister with 60 pre-metered doses of powder blend.

Pack sizes:

1, 2, 3, 4, 5, 6 or 10 devices containing 60 doses

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.