4.1. Therapeutic indications

Asthma

Serevent is indicated for the 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.

Serevent is also indicated in the prevention of exercise-induced asthma.

Chronic Obstructive Pulmonary Disease (COPD)

Serevent is indicated in the treatment of patients with COPD.

4.2. Posology and method of administration

Posology

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 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

Adults aged 18 years and over:

Two actuations of 25 micrograms salmeterol twice daily.

Paediatric population

There is no relevant indication for use of Serevent Evohaler in the paediatric population in the indication for COPD.

Special populations

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.

Method of administration

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.

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 two puffs 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 stages5, 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.

4.3. Contraindications

Hypersensitivity to salmeterol xinafoate or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

The management of asthma should normally follow a stepwise programme.

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

Serevent 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.

Increasing use of short-acting bronchodilators to relieve asthma symptoms indicates deterioration of asthma control. In this case, the patient should be instructed to seek medical advice.

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.

Paradoxical bronchospasm

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 4.8).

The pharmacological side effects of beta-2 agonist treatment, such as tremor, subjective palpitations and headache have been reported, but tend to be transient and to reduce with regular therapy (see section 4.8).

Cardiovascular effects

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.

Thyrotoxicosis

Serevent should be administered with caution in patients with thyrotoxicosis.

Blood glucose levels

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.

Hypokalaemia

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.

Respiratory-related events

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.

Ketoconazole

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).

Inhaler technique

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.

4.5. Interaction with other medicinal products and other forms of interaction

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 micrograms 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 (50 micrograms inhaled twice daily) in 15 healthy subjects for 6 days resulted in a small but non-statistically significant increase in salmeterol exposure (1.4-fold Cmax and 1.2-fold AUC). Co-administration with erythromycin was not associated with any serious adverse effects.

4.6. Pregnancy and lactation

Pregnancy

A moderate amount of clinical data on pregnant women (between 300 to 1000 pregnancy outcomes) indicate no malformative or feto/ neonatal toxicity of salmeterol.

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.

Breast-feeding

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.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <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 50 micrograms twice daily. Frequencies at the higher dose of 100 micrograms twice daily have also been taken to account where appropriate.

System Organ Class

Adverse Reaction

Frequency

Immune System Disorders

Hypersensitivity reactions with the following manifestations:Rash (itching and redness)Anaphylactic reactions including oedema and angioedema, bronchospasm and anaphylactic shock

UncommonVery Rare

Metabolism & Nutrition Disorders

Hypokalaemia Hyperglycaemia

RareVery Rare

Psychiatric Disorders

NervousnessInsomnia

UncommonRare

Nervous System Disorders

Headache (see section 4.4)Tremor (see section 4.4)Dizziness

Common

CommonRare

Cardiac Disorders

Palpitations (see section 4.4)TachycardiaCardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles).

CommonUncommonVery Rare

Respiratory, Thoracic & Mediastinal Disorders

Oropharyngeal irritationParadoxical bronchospasm (see section 4.4)

Very RareVery Rare

Gastrointestinal Disorders

Nausea

Very Rare

Musculoskeletal & Connective Tissue Disorders

Muscle crampsArthralgia

CommonVery Rare

General Disorders and Administration Site Conditions

Non-specific chest pain

Very Rare

The pharmacological side effects of beta2 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 50 micrograms twice daily.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Symptoms and signs

The signs and symptoms of salmeterol overdose are those typical of beta2-adrenergic stimulation including dizziness, increases in systolic blood pressure, tremor, headache and tachycardia.

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

Treatment

If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Further management should be as clinically indicated or as recommended by the national poisons centre, where available.