4.1. Therapeutic indications

Salmeterol is a selective β2-agonist indicated for reversible airways obstruction in patients with asthma and chronic obstructive pulmonary disease (COPD).

In asthma (including nocturnal asthma and exercise induced symptoms) it is indicated for those treated with inhaled corticosteroids who require a long-acting beta agonist in accordance with current treatment guidelines.

Serevent Accuhaler is not a replacement for inhaled or oral corticosteroids which should be continued at the same dose, and not stopped or reduced, when treatment with Serevent Accuhaler is initiated.

4.2. Posology and method of administration

Serevent Accuhaler is for inhalation use only.

Serevent Accuhaler should be used regularly. The full benefits of treatment will be apparent after several doses of the drug.

In reversible airways obstruction such as asthma

Adults (including the elderly): One inhalation (50 micrograms) twice daily, increasing to two inhalations (2 x 50 micrograms) twice daily if required.

Children 4 years and over: One inhalation (50 micrograms) twice daily.

The dosage or frequency of administration should only be increased on medical advice.

There are insufficient clinical data to recommend the use of Serevent Accuhaler in children under the age of four.

In chronic obstructive pulmonary disease

Adults (including the elderly): One inhalation (50 micrograms) twice daily.

Children: Not appropriate.

Special patient groups: There is no need to adjust the dose in patients with impaired renal function.

Using the Accuhaler:

The Accuhaler should be used in a standing or sitting position. The device is opened and primed by sliding the lever. The mouthpiece is then placed in the mouth and the lips closed round it. The dose can then be inhaled and the device closed.

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

Serevent 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 bronchodilators, in particular short-acting inhaled β2-agonists, to relieve 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 Accuhaler 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 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

Beta-adrenergic blockers may weaken or antagonise the effect of salmeterol. Both non-selective and selective β-blockers should be avoided unless there are compelling reasons for their use.

Potentially serious hypokalaemia may result from β2-agonist therapy. Particular caution is advised in acute severe asthma as this effect may be potentiated by hypoxia and by concomitant treatment with xanthine derivatives, steroids and diuretics.

Potent CYP3A4 inhibitors

Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 mcg inhaled twice daily) in 15 healthy subjects for 7 days resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC). This may lead to an increase in the incidence of other systemic effects of salmeterol treatment (e.g. prolongation of QTc interval and palpitations) compared with salmeterol or ketoconazole treatment alone (see section 4.4).

Clinically significant effects were not seen on blood pressure, heart rate, blood glucose and blood potassium levels. Co-administration with ketoconazole did not increase the elimination half-life of salmeterol or increase salmeterol accumulation with repeat dosing.

The concomitant administration of ketoconazole should be avoided, unless the benefits outweigh the potentially increased risk of systemic side effects of salmeterol treatment. There is likely to be a similar risk of interaction with other potent CYP3A4 inhibitors (e.g. itraconazole, telithromycin, ritonavir).

Moderate CYP 3A4 inhibitors

Co-administration of erythromycin (500mg orally three times a day) and salmeterol (50µg inhaled twice daily) in 15 healthy subjects for 6 days resulted in a small but non-statistically significant increase in salmeterol exposure (1.4-fold Cmax and 1.2-fold AUC). Co-administration with erythromycin was not associated with any serious adverse effects.

4.6. Fertility, 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.

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), 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.

System Organ Class

Adverse Reaction

Frequency

Immune System Disorders

Hypersensitivity reactions with the following manifestations:

Rash (itching and redness)

Uncommon

Anaphylactic reactions including oedema and angioedema,bronchospasm and anaphylactic shock

Very Rare

Metabolism & Nutrition Disorders

Hypokalaemia

Rare

Hyperglycaemia

Very Rare

Psychiatric Disorders

Nervousness

Uncommon

Insomnia

Rare

Nervous System Disorders

Headache (see section 4.4)

Common

Tremor (see section 4.4)

Common

Dizziness

Rare

Cardiac Disorders

Palpitations (see section 4.4)

Common

Tachycardia

Uncommon

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

Very Rare

Respiratory, Thoracic & Mediastinal Disorders

Oropharyngeal irritation

Very Rare

Paradoxical bronchospasm (see section 4.4)

Very rare

Gastrointestinal Disorders

Nausea

Very Rare

Musculoskeletal & Connective Tissue Disorders

Muscle cramps

Common

Arthralgia

Very Rare

General Disorders and Administration Site Conditions

Non-specific chest pain

Very Rare

The pharmacological side effects of β2-agonist treatment, such as tremor, subjective palpitations and headache, have been reported, but tend to be transient and to reduce with regular therapy. Tremor and tachycardia occur more commonly when administered at doses higher than 50mcg twice daily.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Symptoms and signs

The signs and symptoms of salmeterol overdosage are those typical of excessive β2-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.