- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyRoute of administration: Inhalation use.Patients should be made aware that Seretide Evohaler must be used daily for optimum benefit, even when asymptomatic.Patients should be regularly reassessed by a doctor, so that the strength of Seretide 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 Seretide 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 Seretide containing the appropriate fluticasone propionate dosage for the severity of their disease. Note: Seretide 25 microgram /50 microgram strength is not appropriate for adults and children with severe asthma. If an individual patient should require dosages outside the recommended regimen, appropriate doses of β2 agonist and/or corticosteroid should be prescribed.
Adults and adolescents 12 years and older:- Two inhalations of 25 micrograms salmeterol and 50 micrograms fluticasone propionate twice daily.or- Two inhalations of 25 micrograms salmeterol and 125 micrograms fluticasone propionate twice daily.or- Two inhalations of 25 micrograms salmeterol and 250 micrograms fluticasone propionate twice daily.A short-term trial of Seretide 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 two inhalations of 25 micrograms salmeterol and 50 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. Seretide is not intended for the initial management of mild asthma. Seretide 25 micrograms /50 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 populationChildren 4 years and older:- Two inhalations of 25 micrograms salmeterol and 50 micrograms fluticasone propionate twice daily.The maximum licensed dose of fluticasone propionate delivered by Seretide inhaler in children is 100 microgram twice daily.There are no data available for use of Seretide inhaler in children aged under 4 years.Children <12 years old may have difficulties synchronising aerosol actuation with inspiration of breath. Use of a spacer device with Seretide inhaler is recommended in patients who have, or are likely to have difficulties to coordinate actuation with inspiration. A recent clinical study has shown that paediatric patients using a spacer achieved exposure similar to adults not using spacer and paediatric patients using Diskus, confirming that spacers compensate for poor inhaler technique (see section 5.2). Either the Volumatic or AeroChamber Plus spacer device can be used (depending on National Guidance). Limited data are available that demonstrate an increase in systemic exposure when the AeroChamber Plus spacer device is used compared with the Volumatic spacer device (see section 4.4).Patients should be instructed in the proper use and care of their inhaler and spacer and their technique checked to ensure optimum delivery of the inhaled drug to the lungs. Patients should continue to use the same make of spacer device as switching between spacer devices can result in changes in the dose delivered to the lungs (see section 4.4). Re-titration to the lowest effective dose should always follow the introduction or change of a spacer device.
Special patient groupsThere is no need to adjust the dose in elderly patients or in those with renal impairment. There are no data available for use of Seretide in patients with hepatic impairment.Instructions for UsePatients should be instructed in the proper use of their inhaler (see patient information leaflet)During inhalation, the patient should preferably sit or stand. The inhaler has been designed for use in a vertical position.Testing the inhaler:Before using for the first time patients should remove the mouthpiece cover by gently squeezing the sides of the cover, shake the inhaler well, hold the inhaler between the fingers and thumb with their thumb on the base, below the mouthpiece and release puffs into the air until the counter reads 120 to make sure that it works. The inhaler should be shaken immediately before releasing each puff. If the inhaler has not been used for a week or more the mouthpiece cover should be removed, the patient should shake the inhaler well and should release two puffs into the air. Each time the inhaler is activated the number on the counter will count down by one.Use of the inhaler:1. Patients should remove the mouthpiece cover by gently squeezing the sides of the cover 2. Patients should check inside and outside of the inhaler including the mouthpiece for the presence of loose objects.3. Patients should shake the inhaler well to ensure that any loose objects are removed and that the contents of the inhaler are evenly mixed4. Patients should hold the inhaler upright between fingers and thumb with their thumb on the base, below the mouthpiece.5. Patients should breathe out as far as is comfortable and then place the mouthpiece in their mouth between their teeth and close their lips around it, Patients should be instructed not to bite the mouth piece.6. Just after starting to breathe in through their mouth, patients should press firmly down on the top of the inhaler to release Seretide, while still breathing in steadily and deeply. 7. While holding their breath, patients should take the inhaler from their mouth and take their finger from the top of the inhaler. Patients should continue holding their breath for as long as is comfortable.8. To take a second inhalation, patients should keep the inhaler upright and wait about half a minute before repeating steps 3 to 7.9. Patients should immediately replace the mouthpiece cover in the correct orientation by firmly pushing and snapping the cap into position. This does not require excessive force, the cover should click into position.IMPORTANTPatients should not rush stages 5, 6 and 7. It is important that patients start to breathe in as slowly as possible just before operating their inhaler. Patients should practise in front of a mirror for the first few times. If they see "mist" coming from the top of their inhaler or the sides of their mouth they should start again from stage 3.Patients should rinse their mouth out with water and spit out, and/or brush their teeth after each dose of medicine, in order to minimise the risk of oropharyngeal candidiasis and hoarseness.Patients should consider getting a replacement when the counter shows the number 020. The counter will stop at 000 when all the recommended puffs have been used. Replace the inhaler when the counter reads 000.Patients should never try to alter the numbers on the counter or detach the counter from the metal canister. The counter cannot be reset and is permanently attached to the canister.Cleaning (also detailed in patient information leaflet):Your inhaler should be cleaned at least once a week. 1. Remove the mouth piece cover.2. Do not remove the canister from the plastic casing.3. Wipe the inside and outside of the mouthpiece and the plastic casing with a dry cloth or tissue.4. Replace the mouthpiece cover in the correct orientation. This does not require excessive force, the cover should click into position.DO NOT PUT THE METAL CANISTER IN WATER
Paediatric populationChildren 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.
Potent CYP3A4 inhibitorsCo-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 inhibitorsCo-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.
FertilityThere are no data in humans. However, animal studies showed no effects of salmeterol or fluticasone propionate on fertility.
PregnancyA moderate amount of data on pregnant women (between 300 to 1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of salmeterol and fluticasone propionate. Animal studies have shown reproductive toxicity after administration of β2 adrenoreceptor agonists and glucocorticosteroids (see section 5.3).Administration of Seretide 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.
BreastfeedingIt 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 Seretide therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
|System Organ Class||Adverse Event||Frequency|
|Infections & Infestations||Candidiasis of the mouth and throat Pneumonia Bronchitis||Common Common1,3Common1,3|
|Immune System Disorders||Hypersensitivity reactions with the following manifestations: Cutaneous hypersensitivity reactions Angioedema (mainly facial and oropharyngeal oedema) Respiratory symptoms (dyspnoea) Respiratory symptoms (bronchospasm) Anaphylactic reactions including anaphylactic shock||Uncommon Rare Uncommon Rare Rare|
|Endocrine Disorders||Cushing's syndrome, Cushingoid features, Adrenal suppression, Growth retardation in children and adolescents, Decreased bone mineral density||Rare4|
|Metabolism & Nutrition Disorders||Hypokalaemia Hyperglycaemia||Common3Uncommon4|
|Psychiatric Disorders||Anxiety Sleep disorders Behavioural changes, including psychomotor hyperactivity and irritability (predominantly in children) Depression, aggression (predominantly in children)||Uncommon Uncommon Rare Not Known|
|Nervous System Disorders||Headache Tremor||Very Common1 Uncommon|
|Eye disorder||Cataract Glaucoma||Uncommon Rare4|
|Cardiac Disorders||Palpitations Tachycardia Cardiac arrhythmias (including supraventricular tachycardia and extrasystoles). Atrial fibrillation Angina pectoris||Uncommon Uncommon Rare Uncommon Uncommon|
|Respiratory, Thoracic & Mediastinal Disorders||Nasopharyngitis Throat irritation Hoarseness/dysphonia Sinusitis Paradoxical bronchospasm||Very Common2,3Common Common Common1,3 Rare4|
|Skin and subcutaneous tissue disorders||Contusions||Common1,3|
|Musculoskeletal & Connective Tissue Disorders||Muscle cramps Traumatic fractures Arthralgia Myalgia||Common Common1,3 Common Common|
Description of selected adverse reactionsThe 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. Seretide Evohaler 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 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 candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Seretide Evohaler.
Paediatric populationPossible 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 reactionsReporting 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.
|Pharmacotherapeutic Group:||Adrenergics and other anti-asthmatics.|
Mechanism of action and pharmacodynamic effectsSeretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below.Salmeterol:Salmeterol is a selective long-acting (12 hour) β2 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 β2 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 safetySeretide Asthma clinical trials A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of Seretide 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 Seretide achieved asthma control than patients treated with ICS alone and this control was attained at a lower corticosteroid dose *Well controlled asthma was achieved more rapidly with Seretide than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual well controlled week was 16 days for Seretide 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 Seretide treatment compared to 23 days following treatment with ICS.The overall study results showed:
|Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC) Asthma over 12 months|
|No ICS (SABA alone)||78%||50%||70%||40%|
|Low dose ICS ( ≤500 microgram BDP or equivalent/day)||75%||44%||60%||28%|
|Medium dose ICS (>500 to 1000 microgram BDP or equivalent/day)||62%||29%||47%||16%|
|Pooled results across the 3 treatment levels||71%||41%||59%||28%|
The Salmeterol Multi-center Asthma Research Trial (SMART)SMART was a multi-centre, randomised, double blind, placebo-controlled, parallel group 28-week study in the US which randomised 13,176 patients to salmeterol (50 micrograms twice daily) and 13,179 patients to placebo in addition to the patients' usual asthma therapy. Patients were enrolled if ≥12 years of age, with asthma and if currently using asthma medication (but not a LABA). Baseline ICS use at study entry was recorded, but not required in the study. The primary endpoint in SMART was the combined number of respiratory-related deaths and respiratory-related life-threatening experiences. Key findings from SMART: primary endpoint
|Patient group||Number of primary endpoint events /number of patients||Relative Risk (95% confidence intervals)|
|All patients||50/13,176||36/13,179||1.40 (0.91, 2.14)|
|Patients using inhaled steroids||23/6,127||19/6,138||1.21 (0.66, 2.23)|
|Patients not using inhaled steroids||27/7,049||17/7,041||1.60 (0.87, 2.93)|
|African-American patients||20/2,366||5/2,319||4.10 (1.54, 10.90)|
|Number of secondary endpoint events /number of patients||Relative Risk (95% confidence intervals)|
|Patients using inhaled steroids||10/6127||5/6138||2.01 (0.69, 5.86)|
|Patients not using inhaled steroids||14/7049||6/7041||2.28 (0.88, 5.94)|
|Combined asthma-related death or life-threatening experience|
|Patients using inhaled steroids||16/6127||13/6138||1.24 (0.60, 2.58)|
|Patients not using inhaled steroids||21/7049||9/7041||2.39 (1.10, 5.22)|
|Patients using inhaled steroids||4/6127||3/6138||1.35 (0.30, 6.04)|
|Patients not using inhaled steroids||9/7049||0/7041||*|
Paediatric populationIn trial SAM101667, in 158 children aged 6 to 16 years with symptomatic asthma, the combination of salmeterol/fluticasone propionate is equally efficacious to doubling the dose of fluticasone propionate regarding symptom control and lung function. This study was not designed to investigate the effect on exacerbations.In a trial which randomized children aged 4 to 11 years [n=428], salmeterol/fluticasone propionate Diskus (50/100 microgram, one inhalation twice daily) was compared with salmeterol/fluticasone propionate MDI (25/50 microgram, two inhalations twice daily) over a 12-week treatment period. The adjusted mean change from baseline in mean morning peak expiratory flow over Weeks 1-12 was 37.7L/min in the Diskus group and 38.6L/min in the MDI group. Improvements were also seen in both treatment groups on rescue and symptom free days and nights.
SalmeterolSalmeterol acts locally in the lung therefore plasma levels are not an indication of therapeutic effects. In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma due to the low plasma concentrations at therapeutic doses (approximately 200 picogram/mL or less) achieved after inhaled dosing.Fluticasone propionateThe 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 a lesser degree of systemic exposure to inhaled fluticasone propionate has been observed. Systemic absorption occurs mainly through the lungs and is initially rapid then prolonged. The remainder of the inhaled dose may be swallowed but contributes minimally to systemic exposure due to the low aqueous solubility and pre-systemic metabolism, resulting in oral availability of less than 1%. There is a linear increase in systemic exposure with increasing inhaled dose. The disposition of fluticasone propionate is characterised by high plasma clearance (1150 mL/min), a large volume of distribution at steady-state (approximately 300 L) and a terminal half-life of approximately 8 hours. Plasma protein binding is 91%. 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.The renal clearance of fluticasone propionate is negligible. Less than 5% of the dose is excreted in urine, mainly as metabolites. The main part of the dose is excreted in faeces as metabolites and unchanged drug.
Paediatric populationThe effect of 21 days of treatment with Seretide Inhaler 25/50 microgram (2 inhalations twice daily with or without a spacer) or Seretide Diskus 50/100 microgram (1 inhalation twice daily) was evaluated in 31 children aged 4 to 11 years with mild asthma. Systemic exposure to fluticasone propionate was similar for Seretide Inhaler with spacer (107 pg hr/mL [95% CI: 45.7, 252.2]) and Seretide Diskus (138 pg hr/mL [95% CI: 69.3, 273.2]), but lower for Seretide Inhaler (24 pg hr/mL [95% CI: 9.6, 60.2]). Systemic exposure to salmeterol was similar for Seretide Inhaler, Seretide Inhaler with spacer, and Seretide Diskus (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).
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