SEREFLO Pressurised inhalation, suspension Ref.[50469] Active ingredients: Fluticasone Salmeterol

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

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 Sereflo. Regular review of patients as treatment is stepped down is important. The lowest effective dose of salmeterol and fluticasone propionate should be used (see section 4.2).

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

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

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

There have been very rare reports of increases in blood glucose levels (see section 4.8) and this should be considered when prescribing to patients with a history of diabetes mellitus.

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

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

Systemic effects may occur with any inhaled 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.

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.

Spacer devices

Systemic absorption of salmeterol and fluticasone propionate is largely through the lungs. As the use of a spacer device with a metered dose inhaler may increase drug delivery to the lungs it should be noted that this could potentially lead to an increase in the risk of systemic adverse effects. Only limited data are available investigating the increase seen in drug delivery to the lungs with Sereflo when used with either the Volumatic spacer device or the AeroChamber Plus spacer device. However, a single dose pharmacokinetic study, Study PRC/CRD/13/11 (with spacers washed in detergent solution and drip dried prior to use) has demonstrated that the systemic exposure to salmeterol and fluticasone propionate may be increased almost two-fold when the Volumatic spacer device is used with Sereflo as compared with the AeroChamber Plus spacer device.

Use of a spacer device is recommended only for Sereflo containing salmeterol 25 microgram and fluticasone propionate 250 microgram (the high strength inhaler). A spacer device is not recommended for use with Sereflo containing salmeterol 25 microgram and fluticasone propionate 125 microgram (the mid/lower strength inhaler). If a spacing device is required for this mid/lower strength, the patient will have to change to an alternative fixed-dose combination of salmeterol and fluticasone propionate containing salmeterol 25 microgram and fluticasone propionate 125 microgram which is authorised for use with a spacer device.

Patients should continue to use the same make of spacer device, either the Volumatic spacer device or the AeroChamber Plus spacer device, as switching between spacer devices can result in changes in the dose delivered to the lungs (see section 4.2).

Re-titration to the lowest effective dose should always follow the introduction or change of a spacer device. If a patient has previously used an alternative product and spacing device and is then transferred to these new fixed-dose combination inhalers with or without a spacing device, re-titration of their dose to the lowest effective dose should always be carried out.

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.

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).

There was an increased reporting of lower respiratory tract infections (particularly pneumonia and bronchitis) in a 3 year study in patients with Chronic Obstructive Pulmonary Disease (COPD) receiving salmeterol and fluticasone propionate as a fixed-dose combination administered via the Diskus/Accuhaler compared with placebo (see section 4.8). In a 3 year COPD study, older patients, patients with a lower body mass index (<25kg/m²) and patients with very severe disease (FEV1<30% predicted) were at greatest risk of developing pneumonia regardless of treatment. Physicians should remain vigilant for the possible development of pneumonia and other lower respiratory tract infections in patients with COPD as the clinical features of such infections and exacerbation frequently overlap. If a patient with severe COPD has experienced pneumonia the treatment with Sereflo should be re-evaluated. The safety and efficacy of Sereflo inhaler has not been established in patients with COPD and therefore Sereflo is not indicated for use in the treatment of patients with COPD.

Concomitant use of systemic ketoconazole significantly increases systemic exposure to salmeterol. This may lead to an increase in the incidence of systemic effects (e.g. prolongation in the QTc interval and palpitations). Concomitant treatment with ketoconazole or other potent CYP3A4 inhibitors should therefore be avoided unless the benefits outweigh the potentially increased risk of systemic side effects of salmeterol treatment (see section 4.5).

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

Children and adolescents <16 years taking high doses of fluticasone propionate (typically ≥1000 micrograms/day) may be at particular risk of systemic effects. 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 corticosteroid is regularly monitored. The dose of inhaled corticosteroid should be reduced to the lowest dose at which effective control of asthma is maintained.

Sereflo is only available in two strengths, it is not available in a lower strength containing salmeterol 25 microgram and fluticasone propionate 50 microgram, the strength which would be prescribed for use in children. Furthermore, there are no data available on the use of Sereflo in children 12 years of age or younger or in adolescents aged 13 to 17 years.

Note: Neither of the two available strengths of this fixed-dose combination of salmeterol xinafoate and fluticasone propionate can be used in the management of asthma in children as the maximum authorised dose of fluticasone propionate for use in children is 100 microgram twice daily. This dose of fluticasone propionate can only be attained by use of a lower strength of this fixed-dose combination than is currently available for Sereflo.

The lack of data in the relevant age groups precludes use of Sereflo in children and adolescents younger than 18 years of age.

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

Concomitant use of other β adrenergic containing 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 drug interactions 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 medicinal 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 C_max 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 C_max and 1.2-fold AUC). Co-administration with erythromycin was not associated with any serious adverse effects.

Fertility

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

Pregnancy

Alarge amount of data on pregnant women (more than 1000 pregnancy outcomes) indicate 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 salmeterol and fluticasone propionate 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 salmeterol and fluticasone propionate therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

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

As Sereflo 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 (≥1/1000 to <1/100), rare (≥ 1/10,000 to <1/1000) 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.

¹ Reported commonly in placebo
² Reported very commonly in placebo
³ Reported over 3 years in a COPD study
⁴ See section 4.4

Description of selected adverse reactions

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

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

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

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.

Not Applicable.