FIXKOH AIRMASTER 50 MICROGRAMS / 100 MICROGRAMS / DOSE INHALATION POWDER PRE-DISPENSED - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Fixkoh Airmaster 50 microgram/100 microgram/ dose inhalation powder, predispensed

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each single inhalation provides a delivered dose (the dose leaving the mouthpiece) of 47 micrograms of salmeterol (as salmeterol xinafoate) and 92 micrograms of fluticasone propionate. This corresponds to a pre-metered dose of 50 micrograms of salmeterol (as salmeterol xinafoate) and 100 micrograms fluticasone propionate.

Excipient with known effect

Each delivered dose contains approximately 13 milligrams of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Inhalation powder, pre-dispensed.

Moulded plastic device containing a foil strip with 60 regularly placed blisters. Each blister contains pre-dispensed dose of white to off white inhalation powder.

4.1 Therapeutic indications

Fixkoh Airmaster is indicated in adults and adolescents 12 years of age and older.

Asthma

Fixkoh Airmaster is indicated in the regular treatment of asthma where use of a combination product (long- acting P2 agonist and inhaled corticosteroid) is appropriate:

– patients not adequately controlled with inhaled corticosteroids and ‚as needed‘ inhaled short-acting P2 agonist

or

– patients already adequately controlled on both inhaled corticosteroid and long-acting P2 agonist

Note: Fixkoh Airmaster 50 microgram /100 microgram strength is not appropriate in adults and children with severe asthma.

Chronic Obstructive Pulmonary Disease (COPD)

Fixkoh Airmaster is indicated for the symptomatic treatment of patients with COPD, with a FEV1 < 60 % predicted normal (pre-bronchodilator) and a history of repeated exacerbations, who have significant symptoms despite regular bronchodilator therapy.

4.2 Posology and method of administration

Posology

Patients are to be made aware that Fixkoh Airmaster must be used daily for optimal benefit, even when asymptomatic.

Patients should be regularly reassessed by a doctor, so that the strength of Fixkoh Airmaster 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 P2 agonist could be titrated to Fixkoh Airmaster 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 daytime symptoms the dose should be given in the morning.

Patients should be given the strength of Fixkoh Airmaster 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 P2 agonist and/or corticosteroid should be prescribed.

Recommended Doses:

Asthma

Adults and adolescents 12 years and older:

– One inhalation of 50 micrograms salmeterol and 100 micrograms fluticasone propionate twice daily.

or

– One inhalation of 50 micrograms salmeterol and 250 micrograms fluticasone propionate twice daily.

or

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

A short-term trial of Fixkoh Airmaster 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 one inhalation of 50 micrograms salmeterol and 100 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.

Fixkoh Airmaster is not intended for the initial management of mild asthma. Fixkoh Airmaster 50 microgram/100 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.

Paediatric population

Fixkoh Airmaster is not recommended for use in children aged under 12 years of age. The safety and efficacy of Fixkoh Airmaster in children aged less than 12 years of age has not been established.

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 for use of Fixkoh Airmaster in patients with hepatic impairment.

Method of administration

Inhalation use.

Required training

Fixkoh Airmaster must be used correctly in order to achieve effective treatment. All patients must be advised to read the patient information leaflet carefully and follow the instructions for use as detailed in the leaflet. All patients must be trained by the prescribing health care professional on how to use Fixkoh Airmaster, especially if this is their first time in using this inhaler. This is to ensure that they understand how to use the inhaler correctly.

The use of Fixkoh Airmaster follows three simple steps, which are outlined below:

1. The device is opened by depressing the red safety lock and primed by sliding the light pink (for 50/100 microgram strength) mouthpiece cover until a “click” is heard.

2. The patient must first exhale. The mouthpiece is then placed in the mouth and the lips closed round it. The dose can then be inhaled through the inhaler by breathing in steadily and deeply. The inhaler is then removed from the mouth and the patient must hold their breath for about 10 seconds or as long as is comfortable.

3. The patient must then be instructed to breathe out gently and close the inhaler cover until a “click” is heard.

Patients must also be advised to rinse their mouth afterwards with water and spit it out and/or brush their teeth after inhaling.

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

Deterioration of disease

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

Increased requirements for use of reliever medication (short-acting bronchodilators), or decreased response to reliever medication indicate deterioration of control and patients should be reviewed by a physician.

Sudden and progressive deterioration in control of asthma is potentially lifethreatening 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 Fixkoh Airmaster. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Fixkoh Airmaster should be used (see section 4.2).

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 Fixkoh Airmaster.

Cessation of therapy

Treatment with Fixkoh Airmaster should not be stopped abruptly in patients with asthma due to risk of exacerbation. Therapy should be down-titrated under physician supervision.

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, Fixkoh Airmaster 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.

Cardiovascular effects

Rarely, Fixkoh Airmaster may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses Fixkoh Airmaster 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.

Hyperglycaemia

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. Fixkoh Airmaster should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Beta 2 adrenoreceptor agonists

The pharmacological side effects of p2 agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.

Excipients

Fixkoh Airmaster contains approximately 13 milligram/dose of lactose monohydrate. This amount does not normally cause problems in lactose intolerant people. Th excipient lactose contains small amounts of milk proteins, which may cause allergic reactions.

Systemic corticosteroid 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 Paediatric population sub-heading below for information on the systemic effects of inhaled corticosteroids in children and adolescents). 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 1,000 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.

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.

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

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. There is also an increased risk of systemic side effects when combining fluticasone propionate with other potent CYP3A inhibitors (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 undesirable effects of salmeterol treatment (see section 4.5).

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.

Paediatric population

Fixkoh Airmaster is not recommended for use in children under 12 years of age (see section 4.2).

Adolescents < 16 years taking high doses of fluticasone propionate

(typically > 1,000 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 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 adolescent to a paediatric respiratory specialist.

It is recommended that the height of adolescent receiving prolonged treatment with inhaled corticosteroid is regularly monitored. The dose of inhaled corticosteroid should be reduced to the lowest dose at which effective control of asthma is maintained.

4.5 Interaction with other medicinal products and other forms of interaction

P adrenergic blockers may weaken or antagonise the effect of salmeterol. Both non-selective and selective P blockers should be avoided unless there are compelling reasons for their use. Potentially serious hypokalaemia may result from P2 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 p 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 CYP3A4 in the gut and liver. Hence, clinically significant interactions with other active substances mediated by fluticasone propionate are unlikely.

In an interaction study in healthy subjects with intranasal fluticasone propionate, ritonavir (a highly potent cytochrome CYP3A4 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 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. Combinations 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 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.

4.6 Fertility, Pregnancy and lactation

Fertility

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

Pregnancy

A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicates no malformative or feto/neonatal toxicity related to salmeterol and fluticasone propionate. Animal studies have shown reproductive toxicity after administration of P2 adrenoreceptor agonists and glucocorticos­teroids (see section 5.3).

Administration of Fixkoh Airmaster 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.

Breastfeeding

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 Fixkoh Airmaster therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of safety profile

As Fixkoh Airmaster 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.

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 p2 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. Fixkoh Airmaster 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 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 Fixkoh Airmaster.

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 Fixkoh Airmaster, 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 Fixkoh Airmaster therapy has to be withdrawn due to overdose of the P 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: 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 corticosteroid may be necessary. When stabilised, treatment should be continued with an inhaled corticosteroid at the recommended dose. Refer to section 4.4: risk of adrenal suppression.

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

5.1 Pharmacodynamic properties

Pharmacotherapeutic               ­Adrenergics in combination with corticosteroids

group:                               ­or other drugs, excl. anticholinergics.

ATC code:                   ­R03AK06

Mechanism of action and pharmacodynamic effects

Fixkoh Airmaster 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) ß2 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 ß2 agonists.

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 combinatination(s), salmeterol xinafoate and fluticasone propionate, but studied a previously authorised product; the studies described were not carried out with Fixkoh Airmaster.

Salmeterol/flu­ticasone propionate – Asthma clinical trials

A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3,416 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 to 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 to 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 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 propionate 50/100 micrograms bd may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential (see section 4.2).

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 P 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 to one inhalation twice daily. The small increase in P 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 COPD – clinical trials

TORCH was a 3-year study to assess the effect of treatment with salmeterol/flu­ticasone propionate inhalation powder 50/500 micrograms twice daily, salmeterol inhalation powder 50 micrograms twice daily, fluticasone propionate (FP) inhalation powder 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 FP and 4.7 % for salmeterol/flu­ticasone propionate.

The mean number of moderate to severe exacerbations per year was significantly reduced with salmeterol/flu­ticasone propionate (FP) as compared with treatment with salmeterol, FP and placebo (mean rate in the salmeterol/flu­ticasone propionate group 0.85 compared with 0.97 in the salmeterol group, 0.93 in the FP group and 1.13 in the placebo). 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 FP (95 % CI: 1 % to 16 %, p = 0.024). Salmeterol and FP 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 propionate compared with placebo was –3.1 units (95 % CI: –4.1 to –2.1; p < 0.001) and when compared with salmeterol was –2.2 units (p < 0.001) and when compared with FP 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 FP 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 FP and 8 for salmeterol/flu­ticasone propionate. There was no significant difference in probability of bone fracture (5.1 % placebo, 5.1 % salmeterol, 5.4 % FP 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/FP 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/FP 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 P2 agonists and anticholinergic drugs, salbutamol/ipra­tropium bromide combination products, oral p2 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.

Asthma

The SalmeterolMulti-center Asthma Research Trial (SMART)

The Salmeterol Multi-center Asthma Research Trial (SMART) was a 28-week US study that evaluated the safety of salmeterol compared to placebo added to usual therapy in adult and adolescent subjects. Although there were no significant differences in the primary endpoint of the combined number of respiratory-related deaths and respiratory-related life-threatening experiences, the study showed a significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated with salmeterol versus 3 deaths out of 3,179 patients on placebo). The study was not designed to assess the impact of concurrent inhaled corticosteroid use, and only 47 % of subjects reported ICS use at baseline.

Safety and efficacy of salmeterol-FP versus FP alone in asthma

Two multi-centre 26-week studies were conducted to compare the safety and efficacy of salmeterol-FP versus FP alone, one in adult and adolescent subjects (AUSTRI trial), and the other in paediatric subjects 4–11 years of age (VESTRI trial). For both studies, enrolled subjects had moderate to severe persistent asthma with history of asthma-related hospitalisation or asthma exacerbation in the previous year. The primary objective of each study was to determine whether the addition of LABA to ICS therapy (salmeterol-FP) was non-inferior to ICS (FP) alone in terms of the risk of serious asthma related events (asthma-related hospitalisation, endotracheal intubation, and death). A secondary efficacy objective of these studies was to evaluate whether ICS/LABA (salmeterol-FP) was superior to ICS therapy alone (FP) in terms of severe asthma exacerbation (defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an in-patient hospitalisation or emergency department visit due to asthma that required systemic corticosteroids).

A total of 11,679 and 6,208 subjects were randomized and received treatment in the AUSTRI and VESTRI trials, respectively. For the primary safety endpoint, noninferiority was achieved for both trials (see Table below).

Serious asthma-related events in the 26-Week AUSTRI and VESTRI trials

a If the resulting upper 95 % CI estimate for the relative risk was less than 2.0, then non-inferiority was concluded.

b If the resulting upper 95 % CI estimate for the relative risk was less than 2.675, then non-inferiority was concluded.

For the secondary efficacy endpoint, reduction in time to first asthma exacerbation for salmeterol-FP relative to FP was seen in both studies, however only AUSTRI met statistical significance:

Paediatric population

Fixkoh Airmaster is not indicated in children under 12 years of age(see section 4.2). The studies described below were carried out with a previously authorised product; the studies described were not carried out with Fixkoh Airmaster.

In trial SAM101667, in 158 children aged 6 to 16 years with symptomatic asthma, the combination of salmeterol/ fluticasone propionate 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 salmeterol/flu­ticasone propionate 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.

Fluticasone propionate containing medications in asthma during pregnancy

An observational retrospective epidemiological cohort study utilising electronic health records from the United Kingdom was conducted to evaluate the risk of MCMs following first trimester exposure to inhaled FP alone and salmeterol-FP relative to non-FP containing ICS. No placebo comparator was included in this study.

Within the asthma cohort of 5,362 first trimester ICS-exposed pregnancies, 131 diagnosed MCMs were identified; 1,612 (30 %) were exposed to FP or salmeterol-FP of which 42 diagnosed MCMs were identified. The adjusted odds ratio for MCMs diagnosed by 1 year was 1.1 (95 %CI: 0.5–2.3) for FP exposed vs non-FP ICS exposed women with moderate asthma and 1.2 (95 %CI: 0.7–2.0) for women with considerable to severe asthma. No difference in the risk of MCMs was identified following first trimester exposure to FP alone versus salmeterol-FP. Absolute risks of MCM across the asthma severity strata ranged from 2.0 to 2.9 per 100 FP-exposed pregnancies which is comparable to results from a study of 15,840 pregnancies unexposed to asthma therapies in the General Practice Research Database (2.8 MCM events per 100 pregnancies).

5.2 Pharmacokinetic properties

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 active substance in plasma due to the low plasma concentrations at therapeutic doses (approximately 200 picogram /mL or less) achieved after inhaled dosing.

Fluticasone propionate

The absolute bioavailability of a single dose of inhaled fluticasone propionate in healthy subjects varies between approximately 5 to 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.

Absorption

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 (1,150 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 active substance.

Paediatric population

Fixkoh Airmaster is not indicated for use in children under 12 years of age. The studies described below were carried out with a previously authorised product; the studies described were not carried out with Fixkoh Airmaster.

In a population pharmacokinetic analysis utilizing data from 9 controlled clinical trials with different devices (dry powder inhaler, metered dose inhaler) that included 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 dry powder inhaler 50/100 compared to fluticasone propionate dry powder inhaler 100 were seen.

Geometric Mean Ratio [90 % CI] for the Salmeterol/flu­ticasone propionate vs fluticasone propionate dry powder inhaler Comparison in Children and Adolescent/Adult Populations

The effect of 21 days of treatment with salmeterol/flu­ticasone inhaler 25/50 micrograms (2 inhalations twice daily with or without a spacer) or salmeterol/flu­ticasone dry powder inhaler 50/100 micrograms (1 inhalation twice daily) was evaluated in 31 children aged 4 to 11 years with mild asthma. Systemic exposure to salmeterol was similar for salmeterol/flu­ticasone inhaler, salmeterol/flu­ticasone inhaler with spacer, and salmeterol/flu­ticasone dry powder inhaler (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). Systemic exposure to fluticasone propionate was similar for salmeterol/flu­ticasone inhaler with spacer (107 pg hr/mL [95 % CI: 45.7, 252.2]) and salmeterol/flu­ticasone dry powder inhaler (138 pg hr/mL [95 % CI: 69.3, 273.2]), but lower for salmeterol/flu­ticasone inhaler (24 pg hr/mL [95 % CI: 9.6, 60.2]).”

5.3 Preclinical safety data

The only safety concerns for human use derived from animal studies of salmeterol 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 have shown embryofetal 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. Neither salmeterol xinafoate or fluticasone propionate have shown any potential for genetic toxicity.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate (which contains milk proteins).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Do not store above 30 °C.

6.5 Nature and contents of container

The inhalation powder is contained in blister held on a formed aluminium/OPA/PVC base foil, with a peelable PETP-film/paper/PVC lidding foil. The blister strip is contained in a moulded white plastic device with a light pink (for 50/100 microgram strength) slidable mouthpiece cover, with a red safety lock.

The inhaler is packaged within triple laminated foil pouch consisting of Polyester/ADH/A­luminium/ADH/Po­lyethylene Fil­m.

The plastic devices are available in cardboard containers, which hold:

1 × 60 dose Fixkoh Airmaster

or 2 × 60 dose Fixkoh Airmaster

or 3 × 60 dose Fixkoh Airmaster

or 10 × 60 dose Fixkoh Airmaster

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

The Fixkoh Airmaster releases a powder which is inhaled into the lungs. A dose indicator on the Fixkoh Airmaster indicates the number of doses left. For detailed instructions for use see the Patient Information Leaflet.

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

7 MARKETING AUTHORISATION HOLDER

Thornton & Ross Ltd. (trading as ‘STADA’)

Linthwaite,

Huddersfield,

HD7 5QH,

UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 00240/0547

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

08/01/2020