Serevent Diskhaler


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Serevent Diskhaler


1. Name Of The Medicinal Product

SereventTM DiskhalerTM

2. Qualitative And Quantitative Composition

Disks comprising four regularly spaced double-foil blisters each delivering a mixture of 50 micrograms salmeterol (as xinafoate) and lactose used in a Diskhaler device.

For excipients, see section 6.1

3. Pharmaceutical Form

Inhalation powder.

4. Clinical Particulars 4.1 Therapeutic Indications

Salmeterol is a selective ?2-agonist indicated for reversible airways obstruction in patients with asthma and chronic obstructive pulmonary disease (COPD).

In asthma (including nocturnal asthma and exercise induced symptoms) it is indicated for those treated with inhaled corticosteroids who require a long-acting beta agonist in accordance with current treatment guidelines.

Serevent Diskhaler is not a replacement for inhaled or oral corticosteroids which should be continued at the same dose, and not stopped or reduced, when treatment with Serevent Diskhaler is initiated.

4.2 Posology And Method Of Administration

Serevent Diskhaler is for inhalation use only.

Serevent Diskhaler should be used regularly. The full benefits of treatment will be apparent after several doses of the drug.

In reversible airways obstruction such as asthma

Adults (including the elderly): One blister (50 micrograms) twice daily, increasing to two blisters (2 x 50 micrograms) twice daily if required.

Children 4 years and over: One blister (50 micrograms) twice daily.

The dosage or frequency of administration should only be increased on medical advice.

There are insufficient clinical data to recommend the use of Serevent Diskhaler in children under the age of four.

In chronic obstructive pulmonary disease

Adults (including the elderly): One blister (50 micrograms) twice daily.

Children: Not appropriate.

Special patient groups: There is no need to adjust the dose in patients with impaired renal function.

4.3 Contraindications

Hypersensitivity to any ingredient of the preparation (see section 6.1)

4.4 Special Warnings And Precautions For Use

Salmeterol should not be used (and is not sufficient) as the first treatment for asthma.

Serevent Diskhaler should not be initiated in patients with significantly worsening or acutely deteriorating asthma.

Sudden and progressive deterioration in asthma control is potentially life-threatening and consideration should be given to starting or increasing corticosteroid therapy. Under these circumstances, regular peak flow monitoring may be advisable. For maintenance treatment of asthma Serevent should be given in combination with inhaled or oral corticosteroids.

Serevent Diskhaler is not a replacement for inhaled or oral corticosteroids (see section 4.1). Patients with asthma must be warned not to stop steroid therapy, and not to reduce it without medical advice, even if they feel better on Serevent Diskhaler.

With its relatively slow onset of action Serevent Diskhaler should not be used to relieve acute asthma symptoms, for which an inhaled short-acting bronchodilator is required. Patients should be advised to have such rescue medication available.

Long-acting bronchodilators should not be the only or the main treatment in maintenance asthma therapy (see section 4.1.

Increasing use of bronchodilators, in particular short-acting inhaled ?2-agonists to relieve symptoms, indicates deterioration of asthma control. The patient should be instructed to seek medical advice if short-acting relief bronchodilator treatment becomes less effective, or more inhalations than usual are required. In this situation the patient should be assessed and consideration given to the need for increased anti-inflammatory therapy (e.g. higher doses of inhaled corticosteroid or a course of oral corticosteroid). Severe exacerbations of asthma must be treated in the normal way.

Although Serevent may be introduced as add-on therapy when inhaled corticosteroids do not provide adequate control of asthma symptoms, patients should not be initiated on Serevent during an acute severe asthma exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Serious asthma-related adverse events and exacerbations may occur during treatment with Serevent. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Serevent.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Serevent. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Serevent should be used.

Salmeterol should be administered with caution in patients with thyrotoxicosis.

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.

Cardiovascular effects, such as increases in systolic blood pressure and heart rate, may occasionally be seen with all sympathomimetic drugs, especially at higher than therapeutic doses. For this reason, salmeterol should be used with caution in patients with pre-existing cardiovascular disease.

Potentially serious hypokalaemia may result from ?2-agonist therapy. Particular caution is advised in acute severe asthma as this effect may be potentiated by hypoxia and by concomitant treatment with xanthine derivatives, steroids and diuretics. Serum potassium levels should be monitored in such situations.

Data from a large clinical trial (the Salmeterol Multi-Center Asthma Research Trial, SMART) suggested African-American patients were at increased risk of serious respiratory-related events or deaths when using salmeterol compared with placebo (see section 5.1). It is not known if this was due to pharmacogenetic or other factors. Patients of black African or Afro-Caribbean ancestry should therefore be asked to continue treatment but to seek medical advice if asthma symptoms remained uncontrolled or worsen whilst using Serevent.

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).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Both non-selective and selective ?-blockers should be avoided in patients with reversible obstructive airways disease, unless there are compelling reasons for their use.

Potent CYP3A4 inhibitors

Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 mcg 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 (500mg orally three times a day) and salmeterol (50µg 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 Pregnancy And Lactation

In animal studies, some effects on the fetus, typical for a ?2-agonist, occurred at exposure levels substantially higher than those that occur with therapeutic use. Extensive experience with other ?2-agonists has provided no evidence that such effects are relevant for women receiving clinical doses. As yet, experience of the use of salmeterol during pregnancy is limited. As with any medicine, use during pregnancy should be considered only if the expected benefit to the mother is greater than any possible risk to the fetus.

Plasma levels of salmeterol after inhaled therapeutic doses are negligible, and therefore levels in milk should be correspondingly low. Nevertheless, as there is limited experience of the use of salmeterol in nursing mothers, its use in such circumstances should only be considered if the expected benefit to the mother is greater than any possible risk to the infant.

Studies in lactating animals support the view that salmeterol is likely to be secreted in only very small amounts into breast milk.

4.7 Effects On Ability To Drive And Use Machines

None reported.

4.8 Undesirable Effects

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: very common (

The following frequencies are estimated at the standard dose of 50mcg twice daily. Frequencies at the higher dose of 100mcg twice daily have also been taken to account where appropriate.

System Organ Class

Adverse Reaction


Immune System Disorders

Hypersensitivity reactions with the following manifestations:





Rash (itching and redness)



Bronchospasm and anaphylactic shock

Not known


Oedema and angioedema,

Not known


Metabolism & Nutrition Disorders




Not known


Psychiatric Disorders






Nervous System Disorders









Cardiac Disorders






Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles).

Not known


Respiratory, Thoracic & Mediastinal Disorders

Oropharyngeal irritation

Not known

Paradoxical bronchospasm

Not known


Gastro-Intestinal Disorders


Not known

Musculoskeletal & Connective Tissue Disorders

Muscle cramps



Not known


General Disorders and Administration Site Conditions

Non-specific chest pain

Not known

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing and drop in peak expiratory flow rate (PEFR) after dosing. This responds to a fast-acting inhaled bronchodilator. Serevent Diskhaler should be discontinued immediately, the patient assessed, and if necessary an alternative presentation or therapy should be instituted (see section 4.4).

The pharmacological side-effects of ?2-agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and to reduce with regular therapy. Tremor and tachycardia occur more commonly when administered at doses higher than 50mcg twice daily.

4.9 Overdose

The symptoms and signs of salmeterol overdosage are tremor, headache and tachycardia. Hypokalaemia may occur. Monitor serum potassium levels. The preferred antidote for overdosage with Serevent Diskhaler is a cardioselective ?-blocking agent. Cardioselective ?-blocking drugs should be used with caution in patients with a history of bronchospasm.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

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

These pharmacological properties of salmeterol offer more effective protection against histamine-induced bronchoconstriction and produce a longer duration of bronchodilatation, lasting for at least 12 hours, than recommended doses of conventional short-acting ?2-agonists. In vitro tests have shown that salmeterol is a potent and long-lasting inhibitor of the release from the human lung of mast cell mediators, such as histamine, leukotrienes and prostaglandin D2. In man, salmeterol inhibits the early and late phase response to inhaled allergen; the latter persisting for over 30 hours after a single dose when the bronchodilator effect is no longer evident. Single dosing with salmeterol attenuates bronchial hyper-responsiveness. These properties indicate that salmeterol has additional non-bronchodilator activity, but the full clinical significance is not yet clear. The mechanism is different from the anti-inflammatory effect of corticosteroids, which should not be stopped or reduced when Serevent Diskhaler is prescribed.

Salmeterol has been studied in the treatment of conditions associated with COPD, and has been shown to improve symptoms and pulmonary function, and quality of life. Salmeterol acts as a ?2-agonist on the reversible component of the disease. In vitro salmeterol has also been shown to increase cilial beat frequency of human bronchial epithelial cells, and also reduce a ciliotoxic effect of Pseudomonas toxin on the bronchial epithelium of patients with cystic fibrosis.

Asthma clinical trials

The Salmeterol Multi- centre 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?g twice daily) and 13,179 patients to placebo in addition to the patients' usual asthma therapy. Patients were enrolled if

Key findings from SMART: primary endpoint

Patient group

Number of primary endpoint events /number of patients

Relative Risk

(95% confidence intervals)





All patients



1.40 (0.91, 2.14)

Patients using inhaled steroids



1.21 (0.66, 2.23)

Patients not using inhaled steroids



1.60 (0.87, 2.93)

African-American patients



4.10 (1.54, 10.90)

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

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



Number of secondary endpoint events /number of patients

Relative Risk

(95% confidence intervals)





Respiratory -related death


Patients using inhaled steroids



2.01 (0.69, 5.86)

Patients not using inhaled steroids



2.28 (0.88, 5.94)

Combined asthma-related death or life-threatening experience


Patients using inhaled steroids



1.24 (0.60, 2.58)

Patients not using inhaled steroids



2.39 (1.10, 5.22)

Asthma-related death


Patients using inhaled steroids



1.35 (0.30, 6.04)

Patients not using inhaled steroids




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

COPD clinical trials

TORCH study

TORCH was a 3-year study to assess the effect of treatment with Seretide Diskus 50/500mcg bd, salmeterol Diskus 50mcg bd, fluticasone propionate (FP) Diskus 500mcg bd or placebo on all-cause mortality in patients with COPD. COPD patients with a baseline (pre



N = 1524

Salmeterol 50

N = 1521

FP 500

N = 1534

Seretide 50/500

N = 1533

All cause mortality at 3 years


Number of deaths (%)









Hazard Ratio vs Placebo (CIs)



(0.73, 1.06)


(0.89, 1.27)


(0.68, 1.00 )

p value





Hazard Ratio Seretide 50/500 vs components (CIs)



(0.77, 1.13)


(0.64, 0.93)


p value





1. Non significant P value after adjustment for 2 interim analyses on the primary efficacy comparison from a log-rank analysis stratified by smoking status


There was a trend towards improved survival in subjects treated with Seretide compared with placebo over 3 years however this did not achieve the statistical significance level p

The mean number of moderate to severe exacerbations per year was significantly reduced with Seretide as compared with treatment with salmeterol, FP and placebo (mean rate in the Seretide 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 Seretide compared with placebo was -3.1 units (95% CI: -4.1 to -2.1; p<0.001), compared with salmeterol was -2.2 units (p<0.001) and compared with FP was

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 Seretide (Hazard ratio for Seretide 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 Seretide. There was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% FP and 6.3% Seretide; Hazard ratio for Seretide vs placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248.

5.2 Pharmacokinetic Properties

Salmeterol acts locally in the lung, therefore plasma levels are not predictive of therapeutic effect. In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma because of the very low plasma concentrations (approximately 200 pg/ml or less) achieved after inhaled dosing.

After regular dosing with salmeterol xinafoate, xinafoic acid can be detected in the systemic circulation, reaching steady state concentrations of approximately 100 ng/ml. These concentrations are up to 1000-fold lower than steady state levels observed in toxicity studies. These concentrations in long term regular dosing (more than 12 months) in patients with airways obstruction, have been shown to produce no ill effects.

5.3 Preclinical Safety Data

In reproduction studies in animals, some effects on the fetus, typical of a ?2-agonist, have been observed at very high doses.

Salmeterol xinafoate produced no genetic toxicity in a range of studies using either prokaryotic or eukaryotic cell systems in vitro or in vivo in the rat.

Long-term studies with salmeterol xinafoate, induced class-related benign tumours of smooth muscle in the mesovarium of rats and the uterus of mice. The scientific literature and our own pharmacological studies provide good evidence that these effects are species-specific and have no relevance for clinical use.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Lactose (which contains milk protein).

6.2 Incompatibilities

None reported.

6.3 Shelf Life

2 years when not stored above 25°C.

6.4 Special Precautions For Storage

Do not store above 25°C.

A disk may be kept in the Diskhaler device but the blisters must only be pierced immediately prior to use.

6.5 Nature And Contents Of Container

A circular double-foil disk with four blisters containing the powder mix of salmeterol (as xinafoate) and lactose. The foil disk is inserted into the Diskhaler device.

The following packs are registered: 5, 7, 10, 14, 15 disks alone or with a Diskhaler. Starter pack consisting of a Diskhaler pre-loaded with one disk (with or without a spare disk, peak flow meter and diary card).

The following packs are available: 14 disks alone or with a Diskhaler. 5 disks with a Diskhaler (Hospital only).

6.6 Special Precautions For Disposal And Other Handling

The powdered medicine is inhaled through the mouth into the lungs. The Diskhaler device is loaded with a disk which contains the medicine in individual blisters which are opened as the device is manipulated.

For detailed instructions for use refer to the Patient Information Leaflet in every pack.

7. Marketing Authorisation Holder

Glaxo Wellcome UK Ltd, trading as Allen & Hanburys

Stockley Park West,

Uxbridge, Middlesex, UB11 1BT

8. Marketing Authorisation Number(S)

PL 10949/0069

9. Date Of First Authorisation/Renewal Of The Authorisation

14 October 1996

10. Date Of Revision Of The Text

14 August 2009

Serevent Diskhaler

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