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.
24 months when not stored above 30°C for moderate climates.
18 months when not stored above 30°C for tropical climates.
None reported.
Lactose (which contains milk protein).
In reproduction studies in animals, some effects on the fetus, typical of a β2-agonist, have been observed at very high doses.
Salmeterol xinafoate produced no genetic toxicity in a range of studies using either prokaryotic or eukaryotic cell systems in vitro or in vivo in the rat.
Long term studies with salmeterol xinafoate, induced class-related benign tumours of smooth muscle in the mesovarium of rats and the uterus of mice. The scientific literature and our own pharmacological studies provide good evidence that these effects are species-specific and have no relevance for clinical use.
Pharmacotherapeutic Group: Selective β2-adrenoreceptor agonists.
ATC Code: R03AC12
Salmeterol is a selective long-acting (usually 12 hours) β2-adrenoceptor agonist with a long side-chain which binds to the exo-site of the receptor.
These pharmacological properties of salmeterol offer more effective protection against histamine-induced bronchoconstriction and produce a longer duration of bronchodilatation, lasting for at least 12 hours, than recommended doses of conventional short-acting β2-agonists. In vitro tests have shown that salmeterol is a potent and long-lasting inhibitor of the release from the human lung of mast cell mediators, such as histamine, leukotrienes and prostaglandin D2. In man, salmeterol inhibits the early and late phase response to inhaled allergen; the latter persisting for over 30 hours after a single dose when the bronchodilator effect is no longer evident. Single dosing with salmeterol attenuates bronchial hyper-responsiveness. These properties indicate that salmeterol has additional non-bronchodilator activity, but the full clinical significance is not yet clear. The mechanism is different from the anti-inflammatory effect of corticosteroids, which should not be stopped or reduced when Serevent Accuhaler is prescribed.
Salmeterol has been studied in the treatment of conditions associated with COPD, and has been shown to improve symptoms and pulmonary function, and quality of life. Salmeterol acts as a β2-agonist on the reversible component of the disease. In vitro salmeterol has also been shown to increase cilial beat frequency of human bronchial epithelial cells, and also reduce a ciliotoxic effect of Pseudomonas toxin on the bronchial epithelium of patients with cystic fibrosis.
Asthma Clinical Trials
The Salmeterol Multi-centre Asthma Research Trial (SMART)
SMART was a multi-centre, randomised, double-blind, placebo-controlled, parallel group 28-week study in the US which randomised 13,176 patients to salmeterol (50μg twice daily) and 13,179 patients to placebo in addition to the patients' usual asthma therapy. Patients were enrolled if >12 years of age, with asthma and if currently using asthma medication (but not a LABA). Baseline ICS use at study entry was recorded, but not required in the study. The primary endpoint in SMART was the combined number of respiratory-related deaths and respiratory-related life-threatening experiences.
Key findings from SMART: primary endpoint
| Patient group | Number of primary endpoint events /number of patients | Relative Risk (95% confidence intervals) | |
| salmeterol | placebo | ||
| All patients | 50/13,176 | 36/13,179 | 1.40 (0.91, 2.14) |
| Patients using inhaled steroids | 23/6,127 | 19/6,138 | 1.21 (0.66, 2.23) |
| Patients not using inhaled steroids | 27/7,049 | 17/7,041 | 1.60 (0.87, 2.93) |
| African-American patients | 20/2,366 | 5/2,319 | 4.10 (1.54, 10.90) |
(Risk in bold is statistically significant at the 95% level.)
Key findings from SMART by inhaled steroid use at baseline: secondary endpoints
| Number of secondary endpoint events /number of patients | Relative Risk (95% confidence intervals) | ||
| salmeterol | placebo | ||
| Respiratory -related death | |||
| Patients using inhaled steroids | 10/6127 | 5/6138 | 2.01 (0.69, 5.86) |
| Patients not using inhaled steroids | 14/7049 | 6/7041 | 2.28 (0.88, 5.94) |
| Combined asthma-related death or life-threatening experience | |||
| Patients using inhaled steroids | 16/6127 | 13/6138 | 1.24 (0.60, 2.58) |
| Patients not using inhaled steroids | 21/7049 | 9/7041 | 2.39 (1.10, 5.22) |
| Asthma-related death | |||
| Patients using inhaled steroids | 4/6127 | 3/6138 | 1.35 (0.30, 6.04) |
| Patients not using inhaled steroids | 9/7049 | 0/7041 | * |
(*=could not be calculated because of no events in placebo group. Risk in bold is statistically significant at the 95% level. The secondary endpoints in the table above reached statistical significance in the whole population.) The secondary endpoints of combined all-cause death or life-threatening experience, all cause death, or all cause hospitalisation did not reach statistical significance in the whole population.
COPD clinical trials
TORCH study
TORCH was a 3-year study to assess the effect of treatment with Seretide Diskus 50/500mcg bd, salmeterol Diskus 50mcg bd, fluticasone propionate (FP) Diskus 500mcg bd or placebo on all-cause mortality in patients with COPD. COPD patients with a baseline (pre-bronchodilator) FEV1 <60% of predicted normal were randomised to double-blind medication. During the study, patients were permitted usual COPD therapy with the exception of other inhaled corticosteroids, long-acting bronchodilators and long-term systemic corticosteroids. Survival status at 3 years was determined for all patients regardless of withdrawal from study medication. The primary endpoint was reduction in all cause mortality at 3 years for Seretide vs Placebo.
|
| Placebo N = 1524 | Salmeterol 50 N = 1521 | FP 500 N = 1534 | Seretide 50/500 N = 1533 |
| All cause mortality at 3 years | ||||
| Number of deaths (%) | 231 (15.2%) | 205 (13.5%) | 246 (16.0%) | 193 (12.6%) |
| Hazard Ratio vs Placebo (CIs) p value |
N/A | 0.879 (0.73, 1.06) 0.180 | 1.060 (0.89, 1.27) 0.525 | 0.825 (0.68, 1.00 ) 0.0521 |
| Hazard Ratio Seretide 50/500 vs components (CIs) p value |
N/A | 0.932 (0.77, 1.13) 0.481 | 0.774 (0.64, 0.93) 0.007 | N/A |
1. Non significant P value after adjustment for 2 interim analyses on the primary efficacy comparison from a log-rank analysis stratified by smoking status
There was a trend towards improved survival in subjects treated with Seretide compared with placebo over 3 years however this did not achieve the statistical significance level p≤0.05. The percentage of patients who died within 3 years due to COPD-related causes was 6.0% for placebo, 6.1% for salmeterol, 6.9% for FP and 4.7% for Seretide.
The mean number of moderate to severe exacerbations per year was significantly reduced with Seretide as compared with treatment with salmeterol, FP and placebo (mean rate in the Seretide group 0.85 compared with 0.97 in the salmeterol group, 0.93 in the FP group and 1.13 in the placebo). This translates to a reduction in the rate of moderate to severe exacerbations of 25% (95% CI: 19% to 31%; p<0.001) compared with placebo, 12% compared with salmeterol (95% CI: 5% to 19%, p=0.002) and 9% compared with FP (95% CI: 1% to 16%, p=0.024). Salmeterol and FP significantly reduced exacerbation rates compared with placebo by 15% (95% CI: 7% to 22%; p<0.001) and 18% (95% CI: 11% to 24%; p<0.001) respectively.
Health Related Quality of Life, as measured by the St George's Respiratory Questionnaire (SGRQ) was improved by all active treatments in comparison with placebo. The average improvement over three years for Seretide compared with placebo was -3.1 units (95% CI: -4.1 to -2.1; p<0.001), compared with salmeterol was -2.2 units (p<0.001) and compared with FP was 1.2 units (p=0.017). A 4-unit decrease is considered clinically relevant.
The estimated 3-year probability of having pneumonia reported as an adverse event was 12.3% for placebo, 13.3% for salmeterol, 18.3% for FP and 19.6% for Seretide (Hazard ratio for Seretide vs placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001). There was no increase in pneumonia related deaths; deaths while on treatment that were adjudicated as primarily due to pneumonia were 7 for placebo, 9 for salmeterol, 13 for FP and 8 for Seretide. There was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% FP and 6.3% Seretide; Hazard ratio for Seretide vs placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248.
Salmeterol acts locally in the lung, therefore plasma levels are not predictive of therapeutic effects. In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma because of the very low plasma concentrations at therapeutic doses (approximately 200 pg/ml or less) achieved after inhaled dosing.
After regular dosing with salmeterol xinafoate, xinafoic acid can be detected in the systemic circulation, reaching steady state concentrations of approximately 100 ng/ml. These concentrations are up to 1000-fold lower than steady state levels observed in toxicity studies. These concentrations in long term regular dosing (more than 12 months) in patients with airways obstruction, have been shown to produce no ill effects.
05 March 2014
Glaxo Wellcome UK Ltd
Stockley Park West
Uxbridge
Middlesex
UB11 1BT
Do not store above 30°C.
Store in the original package.
The powder mix of salmeterol xinafoate and lactose is filled into a blister strip consisting of a formed base foil with a peelable foil laminate lid. The foil strip is contained within the Accuhaler device. Pack sizes 28 or 60. Not all pack sizes may be marketed.
PL 10949/0214
The powdered medicine is inhaled through the mouth into the lungs.
The Accuhaler device contains the medicine in individual blisters which are opened as the device is manipulated.
For detailed instructions for use refer to the Patient Information Leaflet in every pack.
Date of first authorisation: 13 July 2000
Date of latest renewal: 16 August 2006
