SOLTEL Pressurised inhalation, suspension Ref.[7089] Active ingredients: Salmeterol

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 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 salmeterol may be introduced as add-on therapy when inhaled corticosteroids do not provide adequate control of asthma symptoms, patients should not be initiated on salmeterol 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 salmeterol. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on salmeterol.

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 salmeterol. Regular review of patients as treatment is stepped down is important. The lowest effective dose of salmeterol 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. Salmeterol therapy should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted (see section 4.8).

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 (see section 4.8).

Thyrotoxicosis

Salmeterol 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.

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.

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 salmeterol.

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. However, a pharmacokinetic study has been undertaken comparing Soltel CFC-free Inhaler 25 micrograms and another marketed salmeterol CFC-free pressurised metered dose inhaler each delivered through the Volumatic spacer device. The results confirm comparable systemic and pulmonary absorption for both products.

Beta adrenergic blockers may weaken or antagonise the effect of salmeterol. Both non-selective and selective β blockers should be avoided in patients with asthma 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 C_max 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 C_max and 1.2-fold AUC). Co-administration with erythromycin was not associated with any serious adverse effects.

Pregnancy

There are limited data (between 300 to 1000 pregnancy outcomes) from the use of salmeterol in pregnant women indicating no malformative or feto/neonatal toxicity.

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 salmeterol 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 salmeterol 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.

Based on the pharmacodynamic profile of salmeterol and reported adverse effects there is no or negligible influence of salmeterol on the ability to drive and use machines.

Adverse effects 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 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:

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

Cardiac disorders

Common: palpitations (see section 4.4)

Uncommon: tachycardia

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

Respiratory, thoracic and mediastinal disorders

Very rare: oropharyngeal irritation and paradoxical bronchospasm (see section 4.4)

Gastrointestinal disorders

Very rare: nausea

Musculoskeletal, connective tissue and bone disorders

Common: muscle cramps

Very rare: arthralgia

General disorders and administration site conditions

Very rare: non-specific chest pain

The pharmacological side effects of β₂ 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 µg 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

Not applicable.