Summary of medicine characteristics - SALMETEROL CFC-FREE 25 MICROGRAMS PER ACTUATION PRESSURISED INHALATION SUSPENSION
Salmeterol CFC-free 25 micrograms per actuation pressurised inhalation, suspension.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each metered dose (ex-valve) contains 25 micrograms of salmeterol (as xinafoate).
This is equivalent to a delivered dose (ex-actuator) of 21 micrograms salmeterol (as xinafoate).
Excipient(s) with known effect: 0.007 micrograms/dose soya lecithin
For the full list of excipients, see section 6.1.
Pressurised inhalation suspension.
Pressurised aluminium canister containing a white suspension sealed with a metering valve, with a mid-green polypropylene actuator and a pale green polypropylene dust
cap.
4.1 Therapeutic indications
Regular symptomatic add-on treatment of reversible airways obstruction in patients with asthma, including those with nocturnal asthma and exercise-induced asthma, who are inadequately, controlled on inhaled corticosteroids in accordance with current treatment guidelines.
Treatment of chronic obstructive pulmonary disease (COPD).
4.2 Posology and method of administration
Inhalation use.
Salmeterol Xinafoate Inhaler 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.
Posology
Salmeterol Xinafoate Inhaler is indicated for use in adults 18 years of age and older only.
Salmeterol Xinafoate Inhaler is not indicated for use in children 12 years of age and younger or adolescents 13 to 17 years of age.
Asthma
Adults – 18 years of age 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.
Paediatric population
The safety and efficacy of Salmeterol Xinafoate Inhaler in children 12 years of age and younger and in adolescents 13 to 17 years of age have not yet been established.
This medicinal product is not recommended for use in children and adolescents under the age of 18 years.
COPD
Adults – 18 years and older
Two actuations of 25 micrograms salmeterol twice daily.
Paediatric population
There is no indication for use of Salmeterol Xinafoate Inhaler in children and adolescents.
Special populations
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 Xinafoate Inhaler in patients with hepatic impairment.
Method of administration
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 and check the mouthpiece inside and outside to see that it is clean.
2. Patients should shake the inhaler well, before use.
3. 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 to7.
9. After use patients should always replace the mouthpiece cover to keep out dust and fluff.
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 their 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.
Salmeterol Xinafoate Inhaler should be used with a Volumatic® spacer device by patients who find it difficult to synchronize aerosol actuation with inspiration of breath which is often the case in 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 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.
4.3 Contraindications
Salmeterol Xinafoate Inhaler is contraindicated in patients with hypersensitivity to salmeterol xinafoate or any of the excipients (see section 6.1).
Salmeterol Xinafoate Inhaler contains soya lecithin and is contraindicated in patients who have peanut or soya allergies.
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 patients with asthma. Its use is complementary to them.
Patients with asthma must be warned not to stop corticosteroid 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 lifethreatening 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.
As with other inhalational therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath and a fall in peak expiratory flow rate (PEFR) after dosing. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straightaway. If the patient experiences paradoxical bronchopasm salmeterol should be discontinued immediately, the patient assessed, and if necessary, alternative therapy instituted (see section 4.8 ).
Salmeterol should be administered with caution in patients with thyrotoxicosis.
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 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.
Potentially serious hypokalaemia may result from p2 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.
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.
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).
Patients 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 Salmeterol Inhaler 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.
4.5 Interaction with other medicinal products and other forms of interaction
Beta adrenergic blockers may weaken or antagonize the effect of salmeterol. Both non-selective and selective P blockers should be avoided in patients with asthma unless there are compelling reasons for their use.
Potentially serious hypokalaemia may result from P2 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.
Concomitant use of other P adrenergic containing drugs can have a potentially additive effect.
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 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 (500 mg 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 Cmax and 1.2-fold AUC). Co-administration with erythromycin was not associated with any serious adverse effects.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are limited data (less than 300 pregnancy outcomes) from the use of salmeterol in pregnant women.
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.
Breastfeeding
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 breastfeeding or to discontinue/abstain from salmeterol therapy taking into account the benefit of breastfeeding 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.
4.7 Effects on ability to drive and use machines
Salmeterol xinafoate has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Adverse reactions 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.
System Organ Class | Adverse Reaction | Frequency |
Immune system disorders | Hypersensitivity reactions with the following manifestations: Rash (itching and redness) Anaphylactic reactions including oedema and angioedema, bronchospasm and anaphylactic shock | Uncommon Very Rare |
Metabolism and nutrition disorders | Hypokalaemia Hyperglycaemia | Rare Very Rare |
Psychiatric disorders | Nervousness Insomnia | Uncommon Rare |
Nervous system disorders | Headache, tremor Dizziness | Common Rare |
Cardiac disorders | Palpitations Tachycardia Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles). | Common Uncommon Very rare |
Respiratory, thoracic and mediastinal Disorders | Oropharyngeal irritation, paradoxical bronchospasm | Very Rare |
Gastro-intestinal disorders | Nausea | Very Rare |
Musculoskeletal and connective tissue disorders | Muscle cramps Arthralgia | Common Very Rare |
General disorders and administration site conditions | Non-specific chest pain | Very Rare |
The pharmacological side effects of P2 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 micrograms twice daily.
As with other inhalational therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath and fall in peak expiratory flow rate (PEFR) after dosing. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straightaway. If the patient experiences paradoxical bronchopasm salmeterol should be discontinued immediately, the patient assessed, and if necessary, alternative therapy instituted (see section 4.4).
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 the Yellow Card Scheme: www.mhra.gov.uk/yellowcard.
4.9 Overdose
4.9 OverdoseSymptoms and signs
The signs and symptoms of salmeterol overdose are those typical of P2 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective P2 adrenoreceptor agonists
ATC code: R03AC12
Salmeterol is a selective long-acting (12 hour) p2 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 bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting p2 agonists. 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 hyperresponsiveness. 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 antiinflammatory effect of corticosteroids which should not be stopped or reduced when salmeterol is prescribed.
Salmeterol has been studied in the treatment of conditions associated with COPD and has been shown to improve symptoms, pulmonary function and quality of life.
Asthma clinical trials
The 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 jig 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 P2 adrenergic 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) | |
salmeterol | placebo | ||
All patients | 50/13176 | 36/13179 | 1.40 (0.91, 2.14) |
Patients using inhaled corticosteroids | 23/6127 | 19/6138 | 1.21 (0.66, 2.23) |
Patients not using inhaled corticosteroids | 27/7049 | 17/7041 | 1.60 (0.87, 2.93) |
African-American patients | 20/2366 | 5/2319 | 4.10 (1.54, 10.90) |
(Risk in bold is statistically significant at the 95% level.)
Key findings from SMART by inhaled corticosteroid 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 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 conticosteroids | 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) |
Asthma-related death | |||
Patients using inhaled corticosteroids | 4/6127 | 3/6138 | 1.35 (0.30, 6.04) |
Patients not using inhaled corticosteroids | 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 a salmeterol/fluticasone propionate dry powder (SFP) 50/500 micrograms combinationtwice daily, salmeterol dry powder 50 micrograms twice daily, fluticasone propionate (FP) dry powder 500 micrograms twice daily or placebo on allcause mortality in patients with COPD. COPD patients with a baseline (prebronchodilator) 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) | N/A | 0.879 (0.73, 1.06) | 1.060 (0.89, 1.27) | 0.825 (0.68, 1.00 ) |
Hazard Ratio SFP 50/500 vs components (CIs) | N/A | 0.932 (0.77, 1.13) | 0.774 (0.64, 0.93) | N/A |
1. Non significant from a log -rank an | v value after adjustment for 2 interim analyses on the primary efficacy comparison alysis stratified by smoking status |
There was a trend towards improved survival in subjects treated with SFP 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 SFP.
The mean number of moderate to severe exacerbations per year was significantly reduced with SFP as compared with treatment with salmeterol, FP and placebo (mean rate in the SFP 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 SFP 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 SFP (Hazard ratio for SFP 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 SFP. There was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% FP and 6.3% SFP; Hazard ratio for SFP vs placebo: 1.22, 95% CI: 0.87 to 1.72, p = 0.248.
5.2 Pharmacokinetic properties
Salmeterol acts locally in the lung and previous studies have suggested that plasma levels are not necessarily an indication of therapeutic effects. In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the active substance in plasma due to the low plasma concentrations at therapeutic doses (approximately 200 picogram/ml or less) achieved after inhaled dosing.
5.3 Preclinical safety data
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Anhydrous ethanol
Soya lecithin (E322)
Norflurane (HFA 134a), a hydrofluoroalkane (non-chlorofluorocarbon) propellant.
This medicinal product does not contain any chlorofluorocarbon propellants.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Store below 30°C.
Do not freeze.
The canister contains a pressurised liquid. Do not expose to temperatures higher than 50°C, protect from direct sunlight. Do not puncture, break or burn even when apparently empty
6.5 Nature and contents of container
Pressurised aluminium canister containing a white suspension sealed with a metering valve, with a mid-green polypropylene actuator and a pale green polypropylene dust cap.
Each canister provides 120 actuations, each actuation containing 25 micrograms of salmeterol (as xinafoate) corresponding to a delivered dose (ex-actuator) of 21 micrograms salmeterol (as xinafoate).
This medicinal product is available in boxes containing 1,2,3,4 or 5 inhalers.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalNo special requirements for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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GU16 7SR, United Kingdom