Update to MA holder contact details - Address change

Section 7 – Change to the MAH trading style: Deletion of “Allen & Hanburys“

CHANGES IN LINE WITH COMPANY CORE DATA SHEET UPDATE SUMMARISED BELOW:

• Section 4.4 Removal of non-core safety text and general medical guidance.
• Section 4.4 Paradoxical bronchospasm and beta agonist treatment information moved from Adverse Reactions to Warnings and Precautions.  
• Section 4.6 Update to pregnancy guidance.  
• Section 4.9 Update to overdosage treatment guidance.

Adverse event reporting details updated and readability for user.

4.4       Special Warnings and Precautions for Use

Removed the necessity for clinical monitoring of patient response by lung function tests.

 

Specified the use in asthmatic patients in the following statements:

Salmeterol is not a replacement for oral or inhaled corticosteroids in asthma.  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.

 

Added the following statement:

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.

 

4.5       Interaction with Other Medicinal Products and Other Forms of Interaction

In the following statement, clarified the quantity of increase in salmeterol exposure:

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.



1.         NAME OF THE MEDICINAL PRODUCT

 

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

 

4.3       Contra-indications

 

Hypersensitivity to any ingredient of the preparation (see Pharmaceutical Particulars – List of Excipients).

 

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

 

4.4       Special Warnings and Precautions for Use

N.B.: In addition to the proposed changes detailed below, it is proposed to re-arrange the order in which these warnings appear in this section of the SPC. Please refer to the clean copy of the proposed revised SPC for that proposed re-arrangement.

 

The management of asthma should normally follow a stepwise programme and patient response should be monitored clinically and by lung function tests.

 

Serevent 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.

 

Sudden and progressive deterioration of asthma is potentially life-threatening and the patient should undergo urgent medical assessment. cConsiderations should be given to increasing corticosteroid therapy. In patients at risk, daily peak flow monitoring should be instituted. 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.

 

Severe asthma requires regular medical assessment, including lung function testing, as patients are at risk of severe attacks and even death.

 

Increasing use of bronchodilators, in particular short-acting inhaled beta-₂ agonists, to relieve asthma symptoms indicates deterioration of asthma control.  If patients find that short-acting relief bronchodilator treatment becomes less effective or they need more inhalations than usual, medical attention must be sought. 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 patients should be reassessed and consideration given to the need for increased anti-inflammatory therapy (e.g. higher doses of inhaled corticosteroids or a course of oral corticosteroids).  Severe exacerbations of asthma must be treated in the normal way. with nebulised or parenteral bronchodilators and parenteral corticosteroids, together with other supportive measures.

 

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.

 

Patients must be warned not to stop steroid therapy and not to reduce it without medical advice even if they feel better on Serevent.

 

Serevent is not designed to relieve Salmeterol should not be used to treat acute asthma symptoms, for which a fast an inhaled and short-acting inhaled bronchodilator (e.g. salbutamol) is required.  Patients should be advised to have such relief medication available product to be used for the relief of acute asthma symptoms available at all times.

 

Data from a large clinical trial (the Salmeterol Multi-Centre 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.

 

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

 

Serevent should be administered with caution to patients with thyrotoxicosis.

 

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.

 

A transient decrease in serum potassium may occur with all sympathomimetic drugs at higher therapeutic doses. Therefore, salmeterol should be used with caution in patients predisposed to low levels of serum potassium.

 

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.

 

It was observed in a drug interaction study that concomitant use of systemic ketoconazole increases exposure to salmeterol. This may lead to prolongation in the QTc interval. Caution should be exercised when strong CYP3A4 inhibitors (e.g. ketoconazole) are co-administered with salmeterol.

 

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.

 

4.5       Interaction with Other Medicinal Products and Other Forms of Interaction

 

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

 

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.

 

Co-administration of ketoconazole and salmeterol resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC) and this may cause a prolongation of the QTc interval.

 

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.

 

4.6       Pregnancy and Lactation

 

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

 

In animal studies, some effects on the foetus, typical for a beta-₂ agonist, occurred at exposure levels substantially higher than those that occur with therapeutic use.  Extensive experience with other beta-₂ agonists has provided no evidence that such effects are relevant for women receiving clinical doses.

 

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 yet, experience of the use of salmeterol during pregnancy is limited.

 

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

 

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 foetus.

 

Plasma levels of salmeterol after inhaled therapeutic doses are low 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.

 

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.

 

4.7       Effects on the Ability to Drive and Use Machines

 

None reported.

 

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

 

4.8       Undesirable Effects

 N.B.: In addition to the proposed changes detailed below, it is proposed to re-arrange the frequencies layout of this section of the SPC. Please refer to the clean copy of the proposed revised SPC for that proposed new layout.

 

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.

 

Immune system disorders:

 

Hypersensitivity reactions with the following manifestations:

 

Uncommon: Rash (itching and redness)

Very rare: Anaphylactic reactions including oedema and angioedema, bronchospasm and anaphylactic shock

 

Metabolism and nutrition disorders:

 

Rare: Hypokalaemia

Very rare: Hyperglycaemia

 

Psychiatric Disorders:

 

Uncommon:     Nervousness

Rare:                Insomnia

 

Nervous system disorders:

 

Common: Tremor and headache

Rare:        Dizziness    

 

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

 

Cardiac disorders:

 

Common: Palpitations

The pharmacological side-effects of beta-₂ agonist treatment, such as subjective palpitations have been reported, but tend to be transient and to reduce with regular therapy. 

 

Uncommon: Tachycardia

Tachycardia occurs more commonly when administered at doses higher than 50 micrograms twice daily.

 

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

 

Respiratory, thoracic and mediastinal disorders:

 

Very rare: Oropharyngeal irritation and paradoxical bronchospasm.

 

As with other inhalational therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing.  This should be treated immediately with a fast-acting inhaled bronchodilator.  Serevent should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.

 

Musculosketal and connective tissue disorders:

 

Common:  Muscle cramps

 

Very rare: Arthralgia.

 

General Disorders and Administration Site Conditions:

 

Very rare: Non-specific chest pain

 

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).

 

4.9       Overdose

 

The expected symptoms and signs of salmeterol over dosage are those typical of excessive beta₂-adrenergic stimulation, including tremor, headache, tachycardia, increases in systolic blood pressure and hypokalaemia.  The preferred antidote for over dosage with Serevent Diskus is a cardio selective beta-blocking agent.  Cardio selective beta-blocking drugs should be used with caution in patients with a history of bronchospasm.

 

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.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1.         NAME OF THE MEDICINAL PRODUCT

 

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

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

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.

 

3.         PHARMACEUTICAL FORM

 

Inhalation powder, pre-dispensed (Inhalation Powder).

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

 

4.         CLINICAL PARTICULARS

 

4.1       Therapeutic Indications

 

Salmeterol is a long acting beta-2¨Cagonist 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).

 

Serevent, as twice-daily regular treatment, can replace a short-acting (4 hour) inhaled bronchodilator (e.g. salbutamol), when it is required more than once a day, or an oral bronchodilator (e.g. salbutamol, theophylline).

 

There is no evidence that salmeterol is a replacement for corticosteroids and these should not be stopped or reduced when salmeterol is prescribed.  In patients not already receiving anti-inflammatory therapy, this should be considered when starting salmeterol.

 

Patients must be warned not to stop steroid therapy or reduce it without medical advice, even if they feel better on Serevent.

 

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

 

Bronchodilators should not be the only or the main treatment in patients with severe or unstable asthma.  Severe asthma requires regular medical assessment as death may occur.  Patients with severe asthma have constant symptoms and frequent exacerbations, with limited physical capacity, and peak expiratory flow (PEF) values below 60% predicted at baseline with greater than 30% variability, usually not returning entirely to normal after a bronchodilator.  These patients will require high dose inhaled (e.g. >1 milligram/day beclomethasone dipropionate) or oral corticosteroid therapy.  With optimal background steroid therapy, Serevent can offer additional symptomatic treatment.  Sudden worsening of symptoms may require increased corticosteroid dosage which should be administered under urgent medical supervision.

 

 

4.4       Special Warnings and Precautions for Use

 

The management of asthma should normally follow a stepwise programme, and patient response should be monitored clinically and by lung function tests.

 

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

 

Sudden and progressive deterioration of asthma is potentially life-threatening and considerations should be given to starting or increasing corticosteroid therapy.  In patients at risk, daily peak flow monitoring should be instituted.

 

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.

 

Bronchodilators should not be the only or the main treatment in patients with severe or unstable asthma.  Severe asthma requires regular medical assessment, including lung function testing, as patients are at risk of severe attacks and even death. Physicians should consider using oral corticosteroid therapy and/or maximum recommended dose of inhaled corticosteroid in these patients.

 

Increasing use of bronchodilators, in particular short-acting inhaled beta-₂ agonists, to relieve symptoms indicates deterioration of asthma control.  If patients find that short-acting relief bronchodilator treatment becomes less effective or they need more inhalations than usual, medical attention must be sought.  In this situation patients should be reassessed and consideration given to the need for increased anti-inflammatory therapy (e.g. higher doses of inhaled corticosteroids or a course of oral corticosteroids).  Severe exacerbations of asthma must be treated in the normal way with nebulised or parenteral bronchodilators and parenteral corticosteroids, together with other supportive measures.

 

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.

 

Serevent 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 Serevent.

 

Serevent is not designed to relieve acute asthma symptoms, for which an inhaled short-acting bronchodilator (e.g. salbutamol) is required.  Patients should be advised to have such relief medication available.

 

Data from a large clinical trial (the Salmeterol Multi-Centre 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.

 

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

 

Serevent should be administered with caution to patients with thyrotoxicosis.

 

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.

 

A transient decrease in serum potassium may occur with all sympathomimetic drugs at higher therapeutic doses. Therefore, salmeterol should be used with caution in patients predisposed to low levels of serum potassium.

 

It was observed in a drug interaction study that concomitant use of systemic ketoconazole increases exposure to salmeterol. This may lead to prolongation in the QTc interval. Caution should be exercised when strong CYP3A4 inhibitors (e.g. ketoconazole) are co-administered with salmeterol.

 

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

 

4.5       Interaction with Other Medicinal Products and Other Forms of Interaction

 

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

 

Co-administration of ketoconazole and salmeterol resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC) and this may cause a prolongation of the QTc interval.

 

 

5.1       Pharmacodynamic Properties

 

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 ¡Ý12 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

Patient group	Number of primary endpoint events /number of patients		Relative Risk (95% confidence intervals)
	salmeterol	placebo
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)

(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)
	salmeterol	placebo
Respiratory -related death
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)
Asthma-related death
Patients using inhaled steroids	4/6127	3/6138	1.35 (0.30, 6.04)
Patients not using inhaled steroids	9/7049	0/7041	*

(*=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. 

 

 

 

 

	Placebo N = 1524	Salmeterol 50 N = 1521	FP 500 N = 1534	Seretide 50/500 N = 1533
All cause mortality at 3 years
Number of deaths (%)	231 (15.2%)	205 (13.5%)	246 (16.0%)	193 (12.6%)
Hazard Ratio vs Placebo (CIs) p value	N/A	0.879 (0.73, 1.06) 0.180	1.060 (0.89, 1.27) 0.525	0.825 (0.68, 1.00 ) 0.0521
Hazard Ratio Seretide 50/500 vs components (CIs) p value	N/A	0.932 (0.77, 1.13) 0.481	0.774 (0.64, 0.93) 0.007	N/A
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¡Ü0.05.

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.

 

 

5.2       Pharmacokinetic Properties

 

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.

 

 

6.3       Shelf Life

 

            24 months 2 years.

 

 

 

5.2     Pharmacokinetic properties

The absolute bioavailability of a single dose of inhaled fluticasone propionate in healthy subjects changed from 10-30% to. 5-11%.

4.4 Special Warnings and Precautions for Use

.......

A transient decrease in serum potassium may occur with all sympathomimetic drugs at higher therapeutic doses. Therefore, salmeterol should be used with caution in patients predisposed to low levels of serum potassium.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.4 Special Warnings and Precautions for Use

The management of asthma should normally follow a stepwise programme, and patient response should be monitored clinically and by lung function tests.

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

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

Sudden and progressive deterioration of asthma is potentially life-threatening and considerations should be given to starting or increasing corticosteroid therapy. In patients at risk, daily peak flow monitoring should be instituted.

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.

Bronchodilators should not be the only or the main treatment in patients with severe or unstable asthma. Severe asthma requires regular medical assessment, including lung function testing, as patients are at risk of severe attacks and even death. Physicians should consider using oral corticosteroid therapy and/or maximum recommended dose of inhaled corticosteroid in these patients.

Increasing use of bronchodilators, in particular short-acting inhaled beta-2 agonists, to relieve symptoms indicates deterioration of asthma control. If patients find that short-acting relief bronchodilator treatment becomes less effective or they need more inhalations than usual, medical attention must be sought. In this situation patients should be reassessed and consideration given to the need for increased anti-inflammatory therapy (e.g. higher doses of inhaled corticosteroids or a course of oral corticosteroids). Severe exacerbations of asthma must be treated in the normal way with nebulised or parenteral bronchodilators and parenteral corticosteroids, together with other supportive measures.

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.

Serevent 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 Serevent.

Serevent is not designed to relieve acute asthma symptoms, for which an inhaled short-acting bronchodilator (e.g. salbutamol) is required. Patients should be advised to have such relief medication available.

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.

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

Serevent should be administered with caution to patients with thyrotoxicosis.

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.

A transient decrease in serum potassium may occur with all sympathomimetic drugs at higher therapeutic doses. Therefore, salmeterol should be used with caution in patients predisposed to low levels of serum potassium

5.1 Pharmacodynamic Properties

 

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.

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 (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

Patient group	Number of primary endpoint events /number of patients	Relative Risk (95% confidence intervals)
	salmeterol	placebo
All patients	50/13,176	36/13,1791.40 (0.91, 2.14)
Patients using inhaled steroids	23/6,127	19/6,1381.21 (0.66, 2.23)
Patients not using inhaled steroids	27/7,049	17/7,0411.60 (0.87, 2.93)
African-American patients	20/2,366	5/2,3194.10 (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)
	salmeterol	placebo
Respiratory -related death
Patients using inhaled steroids	10/6127	5/61382.01 (0.69, 5.86)
Patients not using inhaled steroids	14/7049	6/70412.28 (0.88, 5.94)
Combined asthma-related death or life-threatening experience
Patients using inhaled steroids	16/6127	13/61381.24 (0.60, 2.58)
Patients not using inhaled steroids	21/7049	9/70412.39 (1.10, 5.22)
Asthma-related death
Patients using inhaled steroids	4/6127	3/61381.35 (0.30, 6.04)
Patients not using inhaled steroids	9/7049	0/7041*

(*=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.