Allen & Hanburys Ltd

Serevent Evohaler 25 micrograms per actuation pressurised inhalation suspension.

One metered dose (ex-valve) contains 25 micrograms salmeterol (as xinafoate). This is equivalent to a delivered dose (ex-actuator) of 21 micrograms salmeterol (as xinafoate).

For a full list of excipients, see section 6.1.

Pressurised inhalation suspension.

White to off white suspension sealed in an aluminium canister in a green actuator.

Regular symptomatic add-on treatment of reversible airways obstruction in patients with asthma, including those with nocturnal asthma, who are inadequately controlled on inhaled corticosteroids in accordance with current treatment guidelines. Treatment of chronic obstructive pulmonary disease (COPD). Prevention of exercise-induced asthma.

Serevent Evohaler is for inhalation use only.

Serevent Evohaler should be used regularly. The full benefits of treatment will be apparent after several doses of the medicinal product. As there may be adverse reactions associated with excessive dosing with this class of medicinal product, the dosage or frequency of administration should only be increased on medical advice.

Recommended Doses:

Asthma

Adults and adolescents 12 years and older:

Two actuations of 25 micrograms salmeterol twice daily.

In asthma patients with more severe airways obstruction up to four inhalations of 25 micrograms of salmeterol twice daily may be of benefit.

Children aged 4 years and older:

Two actuations of 25 micrograms salmeterol twice daily.

Children below 4 years of age:

Serevent Evohaler is not recommended for use in children below four years of age due to insufficient data on safety and efficacy.

COPD

Special patient groups:

There is no need to adjust the dose in elderly patients or in those with renal impairment. There are no data available on the use of Serevent Evohaler in patients with hepatic impairment.

INSTRUCTIONS FOR USE:

Patients should be carefully instructed in the proper use of their inhaler (see Patient Information Leaflet).

1. Patients should remove the mouthpiece cover by gently squeezing the sides of the cover.

2. Patients should check inside and outside of the inhaler including the mouthpiece for the presence of loose objects.

3. Patients should shake the inhaler well to ensure that any loose objects are removed and that the contents of the inhaler are evenly mixed. Before using for the first time or if the inhaler has not been used for a week patients should release one puff into the air to make sure that it works.

4. Patients should hold the inhaler upright between fingers and thumb with their thumb on the base, below the mouthpiece.

5. Patients should breathe out as far as is comfortable and then place the mouthpiece in their mouth between their teeth and close their lips around it. Patients should be instructed not to bite the mouthpiece.

6. Just after starting to breathe in through their mouth patients should press down on the top of the inhaler to release salmeterol while still breathing in steadily and deeply.

7. While holding their breath, patients should take the inhaler from their mouth and take their finger from the top of the inhaler. They should continue holding their breath for as long as is comfortable.

8. If patients are going to take a further puff, they should keep the inhaler upright and wait about half a minute before repeating steps 3 to7.

9. After use patients should always replace the mouthpiece cover to keep out dust and fluff.

10. Patients should replace the mouthpiece cover by firmly pushing and snapping the cap into position.

Important:

Patients should not rush stages 5, 6 and 7. It is important that they start to breathe in as slowly as possible just before operating their inhaler.

Patients should practise in front of a mirror for the first few times. If they see "mist" coming from the top of their inhaler or the sides of their mouth they should start again from stage 2.

Serevent Evohaler should be used with a Volumatic spacer device by patients who find it difficult to synchronise aerosol actuation with inspiration of breath which is often the case for children and the elderly.

Cleaning:

The inhaler should be cleaned at least once a week by:

1. Removing the mouthpiece cover.

2. Wiping the inside and outside of the mouthpiece and the plastic casing with a dry cloth or tissue.

3. Replacing the mouthpiece cover.

The canister must not be removed from the plastic casing when cleaning the inhaler.

PATIENTS MUST NOT PUT THE METAL CANISTER INTO WATER.

Serevent Evohaler 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 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.

As systemic absorption is largely through the lungs, the use of a spacer plus metered dose inhaler may vary the delivery to the lungs. It should be noted that this could potentially lead to an increase in the risk of systemic adverse effects so that dose adjustment may be necessary.

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 (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.

Studies of HFA-134a revealed no effects on the reproductive performance and lactation of adult or two successive generations of rats or on the fetal development of rats or rabbits.

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) and 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 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.

Pharmacotherapeutic Group: Selective beta-2-adrenoreceptor agonists.

ATC Code: R03AC12

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 of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting β₂ agonists. 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 salmeterol is prescribed.

Salmeterol has been studied in the treatment of conditions associated with COPD and has been shown to improve symptoms, pulmonary function and quality of life.

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 (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.

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 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 active substance in plasma due to the low plasma concentrations at therapeutic doses (approximately 200 picogram/ml or less) achieved after inhaled dosing.

The only findings in animal studies with relevance for clinical use were the effects associated with exaggerated pharmacological activity.

In reproduction and development toxicity studies with salmeterol xinafoate there were no effects in rats. In rabbits, typical beta-2 agonist embryo fetal toxicity (cleft palate, premature opening of the eye lids, sternebral fusion and reduced ossification rate of the frontal cranial bones) occurred at high exposure levels (approximately 20 times the maximum recommended human daily dose based on the comparison of AUCs).

Salmeterol xinafoate was negative in a range of standard genotoxicity studies.

The non-CFC propellant, norflurane, has been shown to have no toxic effect at very high vapour concentrations, far in excess of those likely to be experienced by patients, in a wide range of animal species exposed daily for periods of up to two years including no effects on the reproductive performance or embryofetal development.

Norflurane (HFA 134a), a hydrofluoroalkane (non-chlorofluorocarbon) propellant

Not applicable.

2 years

Replace the mouthpiece cover firmly and snap it into position.

Do not store above 30° C.

Pressurised container. Do not expose to temperatures higher than 50°C. Do not puncture, break or burn even when apparently empty.

The suspension is contained in an internally lacquered, 8ml aluminium alloy pressurised container sealed with a metering valve. The containers are fitted into plastic actuators incorporating an atomising mouthpiece and fitted with dustcaps. One pressurised container delivers 120 actuations.

No special requirements.

GlaxoSmithKline (Ireland) Limited,

Stonemasons Way,

Rathfarnham,

Dublin 16.

Trading as: Allen & Hanburys

PA 1077/47/5

25^th August 2006

July 2010