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 β2 agonist and inhaled corticosteroid) is appropriate:

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

or

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

β 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 β2 agonist therapy. Particular caution is advised in acute severe asthma as this effect may be potentiated by concomitant treatment with xanthine derivatives, steroids and diuretics.

Concomitant use of other β adrenergic containing 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 β2 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.

System organ class

Adverse event

Frequency

Infections and infestations

Candidiasis of the mouth and throat

Common

Pneumonia (in COPD patients)

Common1, 3, 5

Bronchitis

Common1, 3

Oesophageal candidiasis

Rare

Immune system disorders

Hypersensitivity reactions with the following manifestations:

Cutaneous hypersensitivity reactions

Uncommon

Angioedema (mainly facial and oropharyngeal oedema)

Rare

Respiratory symptoms (dyspnoea)

Uncommon

Respiratory symptoms (bronchospasm)

Rare

Anaphylactic reactions including anaphylactic shock

Rare

Endocrine disorders

Cushing's syndrome, Cushingoid features, Adrenal suppression, Growth retardation in children and adolescents, Decreased bone mineral density

Rare2,4

Metabolism and nutrition disorders

Hypokalaemia

Common3

Hyperglycaemia

Uncommon2,4

Psychiatric disorders

Anxiety

Uncommon

Sleep disorders

Uncommon

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

Rare

Depression, aggression (predominantly in children)

Not Known

Nervous system disorders

Headache

Very Common1

Tremor

Uncommon

Eye disorders

Cataract

Uncommon

Glaucoma

Rare2,4

Vision, blurred (see also section 4.4)

Not Known2,4

Cardiac disorders

Palpitations

Uncommon

Tachycardia

Uncommon

Cardiac arrhythmias (including supraventricular tachycardia and extrasystoles).

Rare

Atrial fibrillation

Uncommon

Angina pectoris

Uncommon

Respiratory, thoracic and mediastinal disorders

Nasopharyngitis

Very Common2, 3

Throat irritation

Common

Hoarseness/dysphonia

Common

Sinusitis

Common1, 3

Paradoxical bronchospasm

Rare2,4

Skin and subcutaneous tissue disorders

Contusions

Common1, 3

Musculoskeletal and connective tissue disorders

Muscle cramps

Common

Traumatic fractures

Common1, 3

Arthralgia

Common

Myalgia

Common

1 Reported commonly in placebo

2 Reported very commonly in placebo

3 Reported over 3 years in a COPD study

4 See section 4.4

5 See section 5.1

Description of selected adverse reactions

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

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting bronchodilator and should be treated straightaway. 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 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: 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.