Serevent Diskhaler

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

Inhalation powder.

Salmeterol is a selective β2-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.

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.

Serevent Diskhaler is contraindicated in patients with hypersensitivity to salmeterol xinafoate or to the excipient (see Section 6.1).

The management of asthma should normally follow a stepwise programme.

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

Salmeterol is not a replacement for oral or inhaled corticosteroids in asthma (see section 4.1). Its use is complementary to them. Asthmatic patients must be warned not to stop steroid therapy, and not to reduce it without medical advice, even if they feel better on salmeterol.

Salmeterol 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 medicinal product to be used for the relief of acute asthma available at all times.

Increasing use of bronchodilators, in particular short-acting inhaled β2-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.

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. Under these circumstances, daily peak flow monitoring may be advisable. For maintenance treatment of asthma salmeterol should be given in combination with inhaled or oral corticosteroids. Long-acting bronchodilators should not be the only or the main treatment in maintenance asthma therapy (see section 4.1.

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 β2-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).

Patients should be instructed in the proper use of their inhaler and their technique checked to ensure optimum delivery of the inhaled medicinal product to the lungs.

Beta-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 hypoxia and by concomitant treatment with xanthine derivatives, steroids and diuretics.

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.

There are limited data (less than 300 pregnancy outcomes) from the use of salmeterol in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity with the exception of evidence of some harmful effects on the fetus at very high dose levels (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Serevent during pregnancy.

Available pharmacodynamic/toxicological data in animals have shown excretion of salmeterol in milk. A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Serevent therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

No studies on the effect on the ability to drive and use machines have been performed.

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: very common ( 1/10), common (1/100 and <1/10), uncommon (1/1000 and <1/100), rare (1/10,000 and <1/1000), very rare (<1/10,000) including isolated reports. Common and uncommon events were generally determined from clinical trial data. The incidence on placebo was not taken into account. Very rare events are generally determined from post-marketing spontaneous data. 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.

The pharmacological side-effects of β2-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.

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 signs and symptoms of salmeterol overdosage are dizziness, increases in systolic blood pressure, tremor, headache and tachycardia. Monitor serum potassium levels. The preferred antidotes are cardioselective β-blocking agents, which should be used with extreme caution in patients with a history of bronchospasm.

Additionally hypokalaemia can occur and therefore serum potassium levels should be monitored. Potassium replacement should be considered.

Salmeterol is a selective long-acting (usually 12 hours) β2-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 β2-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 β2-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 (50μg 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

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

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

(*=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-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 Seretide vs Placebo.

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 p0.05. 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 Seretide.

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 -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 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.

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.

In reproduction studies in animals, some effects on the fetus, typical of a β2-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.

Lactose (which contains milk protein).

None reported.

2 years when not stored above 25°C.

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.

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).

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.

Glaxo Wellcome UK Ltd, trading as Allen & Hanburys

Stockley Park West,

Uxbridge, Middlesex, UB11 1BT

PL 10949/0069

14 October 1996

11 May 2012