Salmeterol

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.

Clinically significant effects were not seen on blood pressure, heart rate, blood glucose and blood potassium levels. Coadministration 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).

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.

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 hypoxia and by concomitant treatment with xanthine derivatives, steroids and diuretics. Serum potassium levels should be monitored in such situations.

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.

Salmeterol should be administered with caution in patients with thyrotoxicosis.

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.

As a precautionary measure, it is preferable to avoid the use of salmeterol 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 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

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

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.