Serevent Evohaler

·         Section 4.4: removal of non-core safety text in the Warnings and Precautions section.

·         Section 4.8 and 4.4: relocating of the paradoxical bronchospasm and pharmacological side effects of beta₂-agonist wording from the Adverse Reactions section to the Warnings and Precautions section.

·         Section 4.6: update to pregnancy data

·         Section 4.8: Update to Adverse Event Reporting information

·         Section 4.9: update to overdosage guidance treatment.

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.

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 in asthma.  Its use is complementary to them.  Asthmatic Ppatients 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.

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.

………………..etc

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) (1.4-fold Cmax and 1.2-fold AUC).  Co-administration with erythromycin was not associated with any serious adverse effects.

SUMMARY OF PRODUCT CHARACTERISTICS

4.5   Interaction with other medicinal products and other forms of interaction

New text highlighted in red:

4.4     Special warnings and precautions for use

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).

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 asthma unless there are compelling reasons for their use.

Potentially serious hypokalaemia may result from ₂ 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 (50g 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.

1.NAME OF THE MEDICINAL PRODUCT

mg has been changes to micrograms

4.2       Posology and method of administration

Addition of practical instructions for Evohaler use

5.2       Pharmacokinetic properties

Fluticasone propionate:

The following line changed from:

The absolute bioavailability of inhaled fluticasone propionate in healthy subjects varies between approximately 10-30 % of the nominal dose depending on the inhalation device used. 

To : The absolute bioavailability of a single dose of inhaled fluticasone propionate in healthy subjects varies between approximately 5-11% of the nominal dose depending on the inhalation device used. 

 6.4      Special precautions for storage

The following line has been added:

Replace the mouthpiece cover firmly and snap it into position.

4.2 Posology and 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.

Recommended Doses:

Asthma

Adults and adolescents 12 years and older:

Two actuations of 25 micrograms salmeterol twice daily.