Allen & Hanburys Ltd

Serevent Diskus, 50 micrograms per metered dose, inhalation powder, pre-dispensed

Serevent Diskus is a moulded plastic device containing a foil strip with regularly placed blisters each containing 50 micrograms of salmeterol as salmeterol xinafoate.

For a full list of excipients, see 6.1.

Inhalation powder, pre-dispensed (Inhalation Powder).

A moulded plastic device containing a foil blisterstrip with individual doses of a white inhalation powder.

Salmeterol is a long acting beta-2–agonist and should be used only as an adjunct to corticosteroids in the management of asthma. With optimal background steroid therapy, salmeterol can offer additional symptomatic treatment. Patients must be warned not to stop therapy or reduce it without medical advice, even if they feel better on salmeterol.

Adults

Salmeterol provides long-lasting (12 hour) bronchodilation in reversible airways obstruction due to asthma, chronic bronchitis, emphysema and Chronic Obstructive Pulmonary Disease (COPD). It is suitable for long-term regular, twice-daily treatment to control symptoms, but in view of its slower onset of action (10 to 20 minutes), it should not be used to relieve acute asthmatic symptoms, for which a faster acting (within 5 minutes) inhaled bronchodilator (e.g. salbutamol) should be given.

Serevent is indicated when a regular bronchodilator is required, and to prevent night-time symptoms and/or day-time fluctuations caused by reversible airways obstruction (e.g. before exercise or unavoidable allergen challenge).

Regular treatment of reversible airways obstruction in asthma including long-lasting prevention of exercise-induced bronchospasm.

Serevent Diskus is administered by the inhaled route only.

In order to gain full therapeutic benefit regular usage of salmeterol is recommended in the treatment of reversible airways obstruction due to asthma, COPD and chronic bronchitis. The onset of effective bronchodilation (>15% improvement in forced expiratory volume in one second (FEV₁)) occurs within 10 to 20 minutes in asthma patients. The full benefits will be apparent after the first few doses of the drug. The bronchodilator effects of salmeterol usually last for 12 hours. This is particularly useful in the treatment of nocturnal symptoms in asthma, COPD and chronic bronchitis, and in the management of exercise induced asthma.

Patients should be instructed not to take additional doses to treat symptoms but to take a short-acting inhaled beta-₂ agonist

As there may be adverse effects associated with excessive dosing of this class of drug, the dosage or frequency of administration should only be increased on medical advice.

The response to starting salmeterol is usually seen within a few days. If such improvement is not seen, the dose of salmeterol required may need to be increased to the maximum dose of 100 micrograms bd. If improvement is still not seen within 1 week of commencing therapy, salmeterol should be withdrawn and alternative therapy instituted.

Adults:

Treatment of asthma, COPD and chronic bronchitis

One inhalation (50 micrograms of salmeterol) twice daily.

In patients with more severe airways obstruction up to 2 inhalations (2 x 50 micrograms of salmeterol) twice daily may be of benefit.

Children:

There are insufficient clinical data at present to recommend the use of salmeterol in children.

Special patient groups:

There is no need to adjust the dose in elderly patients or in those with renal impairment.

Serevent 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 and patient response should be monitored clinically and by lung function tests.

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. Its use is complementary to them. 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 inhaled bronchodilator is required. Patients should be advised to have their medicinal product to be used for the relief of acute asthma symptoms available at all times.

Increasing use of short-acting bronchodilators to relieve asthma 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 with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Beta-adrenergic blockers may weaken or antagonise the effect of salmeterol. Both non-selective and selective beta-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.

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 (Cmax mean ratio was 1.40). 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 events 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) and very rare (<1/10,000) including isolated reports. Common and uncommon events were generally determined from clinical trial data. The incidence of placebo was not taken into account. Very rare events were generally determined from post-marketing spontaneous data.

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

The pharmacological side effects of beta-2 agonist treatment, such as tremor, headache and palpitations 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 inhalational therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and fall in peak expiratory flow rate (PEFR) after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator. Serevent Evohaler should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted (see Section 4.4).

The signs and symptoms of salmeterol overdose are dizziness, increases in systolic blood pressure, tremor, headache and tachycardia. The preferred antidotes are cardioselective beta-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.

Mechanism of action

Salmeterol is a selective long-acting (12 hour) beta-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 to bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-₂ agonists. In vitro tests have shown salmeterol is a potent and long-lasting inhibitor of the release, from 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 Serevent 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 is prescribed.

Asthma clinical trials

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 (50microgram 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 long acting beta agonist (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 (prebronchodilator) 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, longacting 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.

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 < 0.05.

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

In a placebo-controlled, crossover drug interaction study in 15 healthy subjects, co-administration of salmeterol (50 mcg twice daily inhaled) and the CYP3A4 inhibitor ketoconazole (400 mg once daily orally) for 7 days resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC). There was no increase in salmeterol accumulation with repeat dosing. Three subjects were withdrawn from salmeterol and ketoconazole co-administration due to QTc prolongation or palpitations with sinus tachycardia. In the remaining 12 subjects, co-administration of salmeterol and ketoconazole did not result in a clinically significant effect on heart rate, blood potassium or QTc duration.

In reproduction studies in animals, some effects on the foetus, typical of a beta-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.

Lactose monohydrate (which contains milk protein)

Not applicable.

2 years.

Do not store above 30°C.

The inhalation powder is contained in blisters held on a formed PVC coated base, with a peel able foil laminate lid. The strip is contained in a moulded plastic device. The plastic devices are available in cardboard containers which hold 1 x 28 dose and 1 x 60 dose Diskus.

Not all pack sizes may be marketed.

Patients should be carefully instructed in the correct use of the Diskus.

GlaxoSmithKline (Ireland) Limited

Stonemasons Way,

Rathfarnham,

Dublin 16

Trading as:

Allen & Hanburys

PA 1077/47/3

21st January 1997 / 21st January 2007

July 2010