Summary of Product Characteristics Updated 14-Sep-2016 | Fannin UK/Kent Pharma UK Limited
Adults and adolescents 12 years and older:Two actuations of 25 micrograms salmeterol twice daily.In asthma patients with more severe airways obstruction up to four inhalations of 25 micrograms of salmeterol twice daily may be of benefit.
Children below twelve years of age:The safety and efficacy of NeoventTM CFC-free Inhaler 25 micrograms have not been demonstrated in children. Therefore NeoventTM CFC-free Inhaler 25 micrograms should is not recommended for use in children below twelve years of age.
Adults:Two actuations of 25 micrograms salmeterol twice daily.
Children:There is no relevant indication for use of NeoventTM CFC-free Inhaler 25 micrograms in children.
Special patient groups:There is no need to adjust the dose in elderly patients or in those with renal impairment.There are no data available on the use of salmeterol in patients with hepatic impairment.
INSTRUCTIONS FOR USE:Patients should be carefully instructed in the proper use of their inhaler (see Patient Information Leaflet).1. Patients should remove the mouthpiece cover by gently squeezing the sides of the cover.2. Patients should check inside and outside of the inhaler including the mouthpiece for the presence of loose objects and to see that it is clean.3. Patients should shake the inhaler well to ensure that any loose objects are removed and that the contents of the inhaler are evenly mixed. Before using for the first time patients should release two actuations into the air to make sure that it works. After cleaning or if the inhaler has not been used for a week patients should release one actuation into the air.4. In a sitting or standing position, patients should hold the inhaler upright between fingers and thumb with their thumb on the base, below the mouthpiece.5. Patients should breathe out as far as is comfortable and then place the mouthpiece in their mouth between their teeth and close their lips around it. Patients should be instructed not to bite the mouthpiece.6. Just after starting to breathe in through their mouth patients should press down on the top of the inhaler to release salmeterol while still breathing in steadily and deeply.7. While holding their breath, patients should take the inhaler from their mouth and take their finger from the top of the inhaler. They should continue holding their breath for as long as is comfortable.8. If patients are going to take a further actuation, they should keep the inhaler upright and wait about half a minute before repeating steps 2 to 10. 9. After use patients should always replace the mouthpiece cover to keep out dust and fluff.10. The mouthpiece cover is replaced by firmly pushing and snapping the cap into position.
Important:Patients should not rush stages 5, 6 and 7. It is important that they start to breathe in as slowly as possible just before operating their inhaler.Patients should practise in front of a mirror for the first few times. If they see mist coming from the top of their inhaler or the sides of the mouth they should start again from stage 2.People with weak hands may find it easier to hold the inhaler with both hands. Put the two forefingers on top of the inhaler and both thumbs on the base below the mouthpiece. NeoventTM CFC-free Inhaler 25 micrograms should be used with a Volumatic spacer device by patients who find it difficult to synchronise aerosol actuation with inspiration of breath, which is often the case for the elderly. The patient should be referred to the Volumatic instruction leaflet provided with the spacer device, for full details on its correct use. If their inhaler has been exposed to low temperatures, the patient should take the metal canister out of the plastic case and warm it in their hands for a few minutes. Following warming, one actuation should be released into the air prior to use.
Cleaning the inhaler:The inhaler should be cleaned at least once a week by:1. Removing the mouthpiece cover.2. The canister must not be removed from the plastic casing.3. Wiping the inside and outside of the mouthpiece and the plastic holder with a dry cloth or tissue.4. Firing one spray to waste before next use.5. Replacing the mouthpiece cover.PATIENTS MUST NOT PUT THE METAL CANISTER INTO WATER.
Paradoxical bronchospasmAs with other inhalational therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing and fall in 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.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 reduce with regular therapy (see section 4.8).
ThyrotoxicosisSalmeterol should be administered with caution in patients with thyrotoxicosis.
Blood glucose levelsThere 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 effectsCardiovascular 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.
HypokalaemiaPotentially 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 eventsData 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.
KetoconazoleConcomitant 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 techniquePatients should be instructed in the proper use of their inhaler and their technique checked to ensure optimum delivery of the inhaled medicinal drug 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 NeoventTM 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.
Potent CYP3A4 inhibitorsCo-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 µg 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 inhibitorsCo-administration of erythromycin (500mg orally three times a day) and salmeterol (50 µg 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.
PregnancyA moderate amount of clinical data on pregnant women (between 300 to 1000 pregnancy outcomes) indicates no malformative or fero/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 salmeterol during pregnancy.
Breast-feedingAvailable 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.
|Immune system disorders: Hypersensitivity reactions with the following manifestations:|
|Uncommon:||rash (itching and redness)|
|Very rare:||anaphylactic reactions including oedema and angioedema, bronchospasm and anaphylactic shock|
|Metabolism and nutrition disorders:|
|Nervous system disorders:|
|Common:||tremor and headache|
|Very rare:||cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles)|
|Respiratory, thoracic and mediastinal disorders:|
|Very rare:||oropharyngeal irritation paradoxical bronchospasm (see section 4.4)|
|Musculoskeletal, connective tissue and bone disorders:|
|General disorders and administration site conditions:|
|Very rare:||non-specific chest pain|
Reporting of suspected adverse reactionsReporting 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.
SymptomsThe signs and symptoms of a salmeterol overdose are those typical of beta-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.
ManagementIf 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.The preferred antidotes are cardioselective β blocking agents, which should be used with extreme caution in patients with a history of bronchospasm.
|Pharmacotherapeutic group:||Selective β2 adrenoceptor agonists|
Asthma Clinical TrialsThe Salmeterol Multi-center 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 (50 µg 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 long-acting β2 agonist - LABA). Baseline inhaled corticosteroid (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)|
|All patients||50/13,176||36/13,179||1.40 (0.91, 2.14)|
|Patients using inhaled corticosteroids||23/6,127||19/6,138||1.21 (0.66, 2.23)|
|Patients not using inhaled corticosteroids||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)|
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)|
|Respiratory -related death|
|Patients using inhaled corticosteroids||10/6127||5/6138||2.01 (0.69, 5.86)|
|Patients not using inhaled corticosteroids||14/7049||6/7041||2.28 (0.88, 5.94)|
|Combined asthma-related death or life-threatening experience|
|Patients using inhaled corticosteroids||16/6127||13/6138||1.24 (0.60, 2.58)|
|Patients not using inhaled corticosteroids||21/7049||9/7041||2.39 (1.10, 5.22)|
|Patients using inhaled corticosteroids||4/6127||3/6138||1.35 (0.30, 6.04)|
|Patients not using inhaled corticosteroids||9/7049||0/7041||*|
COPD clinical trials
TORCH studyTORCH was a 3-year study to assess the effect of treatment with a salmeterol/fluticasone propionate dry powder (SFP) 50/500 µg combination bd, salmeterol dry powder 50 µg bd, fluticasone propionate (FP) dry powder 500 µg 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 SFP vs Placebo.
|Placebo N = 1524||Salmeterol 50 N = 1521||FP 500 N = 1534||SFP 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 SFP 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|
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