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SUMMARY OF PRODUCT CHARACTERISTICS
4.4 Special warnings and precautions for use
Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained.
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored.
Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children and adolescents <16years taking high doses of fluticasone propionate (typically ³ 1000mcg/day) may be at particular risk. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of fluticasone propionate between 500 and less than 1000mcg. Situations, which could potentially trigger acute adrenal crisis include trauma, surgery, infection or any rapid reduction in dosage. Presenting symptoms are typically vague and may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, hypotension, decreased level of consciousness, hypoglycaemia, and seizures. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.
(cont‘d)
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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).
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Paediatric Population
Children and adolescents <16years taking high doses of fluticasone propionate (typically ³ 1000mcg/day) may be at particular risk. Systemic effects may occur, particularly at high doses prescribed for long periods. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, acute adrenal crisis and growth retardation in children and adolescents. It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored. The dose of inhaled corticosteroid should be reduced to the lowest dose at which effective control of asthma is maintained.
Children and adolescents <16years taking high doses of fluticasone propionate (typically ³ 1000mcg/day) may be at particular risk. Systemic effects may occur, particularly at high doses prescribed for long periods. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, acute adrenal crisis and growth retardation in children and adolescents.
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored. The dose of inhaled corticosteroid should be reduced to the lowest dose at which effective control of asthma is maintained.
4.6 Pregnancy and lactation
There are insufficient data on the use of salmeterol and fluticasone propionate during pregnancy and lactation in man to assess the possible harmful effects. In animal studies foetal abnormalities occur after administration of beta-2-adrenoreceptor agonists and glucocorticosteroids (see section 5.3).
Administration of Seretide to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.
The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women.
There are no data available for human breast milk. Both salmeterol and fluticasone propionate are excreted into breast milk in rats. Administration of Seretide to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.
4.6 Fertility, pregnancy and lactation
Fertility There are no data in humans. However, animal studies showed no effects of salmeterol or fluticasone propionate on fertility. Pregnancy A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of salmeterol and fluticasone propionate. Animal studies have shown reproductive toxicity after administration of beta-2-adrenoreceptor agonists and glucocorticosteroids (see section 5.3). There are insufficient data on the use of salmeterol and fluticasone propionate during pregnancy and lactation in man to assess the possible harmful effects. In animal studies foetal abnormalities occur after administration of beta-2-adrenoreceptor agonists and glucocorticosteroids (see section 5.3). Administration of Seretide to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus. The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women. Lactation There are no data available for human breast milk. Both salmeterol and fluticasone propionate are excreted into breast milk in rats. Administration of Seretide to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child. It is unknown whether salmeterol and fluticasone propionate/metabolites are excreted in human milk. Studies have shown that salmeterol and fluticasone propionate, and their metabolites, are excreted into the milk of lactating rats. A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Seretide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
There are no data in humans. However, animal studies showed no effects of salmeterol or fluticasone propionate on fertility. Pregnancy A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of salmeterol and fluticasone propionate. Animal studies have shown reproductive toxicity after administration of beta-2-adrenoreceptor agonists and glucocorticosteroids (see section 5.3). There are insufficient data on the use of salmeterol and fluticasone propionate during pregnancy and lactation in man to assess the possible harmful effects. In animal studies foetal abnormalities occur after administration of beta-2-adrenoreceptor agonists and glucocorticosteroids (see section 5.3). Administration of Seretide to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus. The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women. Lactation There are no data available for human breast milk. Both salmeterol and fluticasone propionate are excreted into breast milk in rats. Administration of Seretide to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child. It is unknown whether salmeterol and fluticasone propionate/metabolites are excreted in human milk. Studies have shown that salmeterol and fluticasone propionate, and their metabolites, are excreted into the milk of lactating rats. A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Seretide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
There are no data in humans. However, animal studies showed no effects of salmeterol or fluticasone propionate on fertility.
Pregnancy
A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of salmeterol and fluticasone propionate. Animal studies have shown reproductive toxicity after administration of beta-2-adrenoreceptor agonists and glucocorticosteroids (see section 5.3).
There are insufficient data on the use of salmeterol and fluticasone propionate during pregnancy and lactation in man to assess the possible harmful effects. In animal studies foetal abnormalities occur after administration of beta-2-adrenoreceptor agonists and glucocorticosteroids (see section 5.3). Administration of Seretide to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus. The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women. Lactation There are no data available for human breast milk. Both salmeterol and fluticasone propionate are excreted into breast milk in rats. Administration of Seretide to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child. It is unknown whether salmeterol and fluticasone propionate/metabolites are excreted in human milk. Studies have shown that salmeterol and fluticasone propionate, and their metabolites, are excreted into the milk of lactating rats. A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Seretide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Administration of Seretide to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus. The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women. Lactation There are no data available for human breast milk. Both salmeterol and fluticasone propionate are excreted into breast milk in rats. Administration of Seretide to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child. It is unknown whether salmeterol and fluticasone propionate/metabolites are excreted in human milk. Studies have shown that salmeterol and fluticasone propionate, and their metabolites, are excreted into the milk of lactating rats. A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Seretide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Lactation
There are no data available for human breast milk. Both salmeterol and fluticasone propionate are excreted into breast milk in rats. Administration of Seretide to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child. It is unknown whether salmeterol and fluticasone propionate/metabolites are excreted in human milk. Studies have shown that salmeterol and fluticasone propionate, and their metabolites, are excreted into the milk of lactating rats. A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Seretide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
It is unknown whether salmeterol and fluticasone propionate/metabolites are excreted in human milk.
Studies have shown that salmeterol and fluticasone propionate, and their metabolites, are excreted into the milk of lactating rats. A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Seretide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Studies have shown that salmeterol and fluticasone propionate, and their metabolites, are excreted into the milk of lactating rats.
A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Seretide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
1. NAME OF THE MEDICINAL PRODUCT
Seretide 100 Diskus 50 microgram/100 microgram/dose inhalation powder, pre-dispensed.
Seretide 250 Diskus 50 microgram/250 microgram/dose inhalation powder, pre-dispensed.
Seretide 500 Diskus 50 microgram/500 microgram/dose inhalation powder, pre-dispensed.
The management of asthma should normally follow a stepwise programme and patient response should be monitored clinically and by lung function tests.
Seretide Diskus should not be used to treat acute asthma symptoms for which a fast and short acting bronchodilator is required. Patients should be advised to have their medicinal product to be used for relief in an acute asthma attack available at all times.
Patients should not be initiated on Seretide during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma.
Serious asthma-related adverse events and exacerbations may occur during treatment with Seretide. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Seretide.
Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician.
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. The patient should also be medically reviewed where the current dosage of Seretide has failed to give adequate control of asthma. Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Seretide. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Seretide should be used (see section 4.2). For patients with asthma or COPD, consideration should be given to additional corticosteroid therapies. Treatment with Seretide should not be stopped abruptly in patients with asthma due to risk of exacerbation. Therapy should be down-titrated under physician supervision. For patients with COPD cessation of therapy may also be associated with symptomatic decompensation and should be supervised by a physician. As with all inhaled medication containing corticosteroids, Seretide should be administered with caution in patients with pulmonary tuberculosis. Rarely, Seretide may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. Therefore Seretide should be used with caution in patients with severe cardiovascular disorders, heart rhythm abnormalities, diabetes mellitus, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium. 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. As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. Seretide Diskus should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary. Seretide contains lactose up to 12.5 milligram /dose. This amount does not normally cause problems in lactose intolerant people. Care should be taken when transferring patients to Seretide therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy. Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained. It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored. Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children and adolescents <16years taking high doses of fluticasone propionate (typically ³ 1000mcg/day) may be at particular risk. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of fluticasone propionate between 500 and less than 1000mcg. Situations, which could potentially trigger acute adrenal crisis include trauma, surgery, infection or any rapid reduction in dosage. Presenting symptoms are typically vague and may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, hypotension, decreased level of consciousness, hypoglycaemia, and seizures. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery. The benefits of inhaled fluticasone propionate therapy should minimise the need for oral steroids, but patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time. Patients who have required high dose emergency corticosteroid therapy in the past may also be at risk. This possibility of residual impairment should always be borne in mind in emergency and elective situations likely to produce stress, and appropriate corticosteroid treatment must be considered. The extent of the adrenal impairment may require specialist advice before elective procedures. Ritonavir can greatly increase the concentration of fluticasone propionate in plasma. Therefore, concomitant use should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects. There is also an increased risk of systemic side effects when combining fluticasone propionate with other potent CYP3A inhibitors (see section 4.5). There was an increased reporting of lower respiratory tract infections (particularly pneumonia and bronchitis) in the TORCH study in patients with COPD receiving Seretide 50/500 micrograms bd compared with placebo as well as in studies SCO40043 and SCO100250 comparing the lower non-approved COPD dose of Seretide, 50/250 micrograms bd, to salmeterol 50 micrograms bd only (see section 4.8 and section 5.1). A similar incidence of pneumonia in the Seretide group was seen across all studies. In TORCH, older patients, patients with a lower body mass index (<25kg/m2) and patients with very severe disease (FEV1<30% predicted) were at greatest risk of developing pneumonia regardless of treatment. Physicians should remain vigilant for the possible development of pneumonia and other lower respiratory tract infections in patients with COPD as the clinical features of such infections and exacerbation frequently overlap. If a patient with severe COPD has experienced pneumonia the treatment with Seretide should be re-evaluated. 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 Seretide. 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). 4.8 Undesirable effects As Seretide contains salmeterol and fluticasone propionate, the type and severity of adverse reactions associated with each of the compounds may be expected. There is no incidence of additional adverse events following concurrent administration of the two compounds. Adverse events which have been associated with salmeterol/fluticasone propionate are given below, listed by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (³1/100 and <1/10), uncommon (³1/1000 and <1/100), rare (³1/10,000 to <1/1000), and very rare (<1/10,000) including isolated reports. Very common, common and uncommon events were derived from clinical trial data. The incidence in placebo was not taken into account. Very rare events were derived from post-marketing spontaneous data. NOTE: The changes to this table relate purely to sequence and layout issues. There are no changes to the adverse events and/or frequency. System Organ Class Adverse Event Frequency Infections & Infestations Cardiac Disorders Candidiasis of the mouth and throat Pneumonia Bronchitis Palpitations Tachycardia Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles). Common Common1,3,5 Common1,3 Common Uncommon Very Rare Immune System Disorders Nervous System Disorders Hypersensitivity reactions with the following manifestations: Cutaneous hypersensitivity reactions Angioedema (mainly facial and oropharyngeal oedema), Respiratory symptoms (dyspnoea and/or bronchospasm), Anaphylactic reactions including anaphylactic shock Headache Tremor Uncommon Very Rare *Very Common Common Endocrine Disorders Eye Disorders Cushing’s syndrome, Cushingoid features, Adrenal suppression, Growth retardation in children and adolescents, Decreased bone mineral density Cataract, Glaucoma Very Rare4 Very Rare Metabolism & Nutrition Disorders Respiratory, Thoracic & Mediastinal Disorders Hypokalaemia Hyperglycaemia Nasopharyngitis Throat irritation Hoarseness/dysphonia Sinusitis Paradoxical bronchospasm Common3 Very Rare4 **#Very Common Common Common *#Common Very Rare Psychiatric Disorders Skin and subcutaneous tissue disorders Anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children) Contusions Very Rare *#Common Nervous System Disorders Musculoskeletal & Connective Tissue Disorders Headache Tremor Muscle cramps Traumatic fractures Arthralgia Myalgia Very Common1 Common Common *#Common Very Rare Very Rare Eye Disorders Endocrine Disorders Cataract, Glaucoma Cushing’s syndrome, Cushingoid features, Adrenal suppression, Growth retardation in children and adolescents, Decreased bone mineral density Very Rare4 Very Rare Cardiac Disorders Metabolism & Nutrition Disorders Palpitations Tachycardia Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles). Hypokalaemia Hyperglycaemia Common Uncommon Very Rare Common Very Rare Respiratory, Thoracic & Mediastinal Disorders Infections & Infestations Nasopharyngitis Throat irritation Hoarseness/dysphonia Sinusitis Paradoxical bronchospasm Candidiasis of the mouth and throat Pneumonia Bronchitis Very Common2,3 Common Common Common1,3 Very Rare4 Common *#Common *#Common Skin and subcutaneous tissue disorders Immune System Disorders Contusions Hypersensitivity reactions with the following manifestations: Cutaneous hypersensitivity reactions Angioedema (mainly facial and oropharyngeal oedema), Respiratory symptoms (dyspnoea and/or bronchospasm), Anaphylactic reactions including anaphylactic shock Common1,3 Uncommon Very Rare Musculoskeletal & Connective Tissue Disorders Psychiatric Disorders Muscle cramps Traumatic fractures Arthralgia Myalgia Anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children) Common Common1,3 Very Rare Very Rare Very Rare 1. Reported commonly in placebo 2. Reported very commonly in placebo 3. Reported over 3 years in a COPD study 4. See section 4.4 5. See section 5.1. Description of selected adverse reactions The pharmacological side effects of beta-2-agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy. Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients. Both hoarseness and incidence of candidiasis may be relieved by gargling with water after using the product. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Seretide Diskus. Pneumonia was reported in studies of patients with COPD (see section 5.1) Paediatric population Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, and growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma (see section 4.4). Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability. There have been very rare reports of hyperglycaemia (see section 4.4). As with other inhalation therapy, paradoxical broncospasm may occur (see section 4.4). 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Adrenergics and other anti-asthmatics. ATC Code: R03AK06 Seretide Asthma clinical trials A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of Seretide versus inhaled corticosteroid (Fluticasone Propionate) alone to determine whether the goals of asthma management were achievable. Treatment was stepped up every 12 weeks until **Total control was achieved or the highest dose of study drug was reached. GOAL showed more patients treated with Seretide achieved asthma control than patients treated with ICS alone and this control was attained at a lower corticosteroid dose. Well Controlled asthma was achieved more rapidly with Seretide than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual Well Controlled week was 16 days for Seretide compared to 37 days for the ICS group. In the subset of steroid naive asthmatics the time to an individual Well Controlled week was 16 days in the Seretide treatment compared to 23 days following treatment with ICS. The overall study results showed: Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC) Asthma over 12 months Pre-Study Treatment Salmeterol/FP FP WC TC WC TC No ICS (SABA alone) 78% 50% 70% 40% Low dose ICS ( ≤500mcg BDP or equivalent/day) 75% 44% 60% 28% Medium dose ICS (>500-1000mcg BDP or equivalent/day) 62% 29% 47% 16% Pooled results across the 3 treatment levels 71% 41% 59% 28% *Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung function plus no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy **Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy The results of this study suggest that Seretide 50/100mcg bd may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential (see section 4.2). A double-blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of Seretide for two weeks. The study showed that doubling the inhalations of each strength of Seretide for up to 14 days resulted in a small increase in beta-agonist-related adverse events (tremor; 1 patient [1%] vs 0, palpitations; 6 [3%] vs 1 [<1%], muscle cramps; 6[3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid related adverse events (e.g. oral candidiasis; 6 [6%] vs 16 [8%], hoarseness; 2 [2%] vs 4 [2%]) compared to one inhalation twice daily. The small increase in beta-agonist-related adverse events should be taken into account if doubling the dose of Seretide is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy. Seretide COPD clinical trials 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. Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of Seretide 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication. Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of Seretide 50/250 micrograms bd (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation. The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies. The results of both studies showed that treatment with Seretide 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured Seretide 50/250 micrograms bd over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the Seretide 50/250 micrograms bd group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with Seretide 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following treatment with Seretide 50/500 micrograms bd in TORCH. 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 (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 figures 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. Mechanism of action: Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
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. The patient should also be medically reviewed where the current dosage of Seretide has failed to give adequate control of asthma.
Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Seretide. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Seretide should be used (see section 4.2).
For patients with asthma or COPD, consideration should be given to additional corticosteroid therapies.
Treatment with Seretide should not be stopped abruptly in patients with asthma due to risk of exacerbation. Therapy should be down-titrated under physician supervision. For patients with COPD cessation of therapy may also be associated with symptomatic decompensation and should be supervised by a physician. As with all inhaled medication containing corticosteroids, Seretide should be administered with caution in patients with pulmonary tuberculosis. Rarely, Seretide may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. Therefore Seretide should be used with caution in patients with severe cardiovascular disorders, heart rhythm abnormalities, diabetes mellitus, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium. 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. As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. Seretide Diskus should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary. Seretide contains lactose up to 12.5 milligram /dose. This amount does not normally cause problems in lactose intolerant people. Care should be taken when transferring patients to Seretide therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy. Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained. It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored. Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children and adolescents <16years taking high doses of fluticasone propionate (typically ³ 1000mcg/day) may be at particular risk. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of fluticasone propionate between 500 and less than 1000mcg. Situations, which could potentially trigger acute adrenal crisis include trauma, surgery, infection or any rapid reduction in dosage. Presenting symptoms are typically vague and may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, hypotension, decreased level of consciousness, hypoglycaemia, and seizures. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery. The benefits of inhaled fluticasone propionate therapy should minimise the need for oral steroids, but patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time. Patients who have required high dose emergency corticosteroid therapy in the past may also be at risk. This possibility of residual impairment should always be borne in mind in emergency and elective situations likely to produce stress, and appropriate corticosteroid treatment must be considered. The extent of the adrenal impairment may require specialist advice before elective procedures. Ritonavir can greatly increase the concentration of fluticasone propionate in plasma. Therefore, concomitant use should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects. There is also an increased risk of systemic side effects when combining fluticasone propionate with other potent CYP3A inhibitors (see section 4.5). There was an increased reporting of lower respiratory tract infections (particularly pneumonia and bronchitis) in the TORCH study in patients with COPD receiving Seretide 50/500 micrograms bd compared with placebo as well as in studies SCO40043 and SCO100250 comparing the lower non-approved COPD dose of Seretide, 50/250 micrograms bd, to salmeterol 50 micrograms bd only (see section 4.8 and section 5.1). A similar incidence of pneumonia in the Seretide group was seen across all studies. In TORCH, older patients, patients with a lower body mass index (<25kg/m2) and patients with very severe disease (FEV1<30% predicted) were at greatest risk of developing pneumonia regardless of treatment. Physicians should remain vigilant for the possible development of pneumonia and other lower respiratory tract infections in patients with COPD as the clinical features of such infections and exacerbation frequently overlap. If a patient with severe COPD has experienced pneumonia the treatment with Seretide should be re-evaluated. 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 Seretide. 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). 4.8 Undesirable effects As Seretide contains salmeterol and fluticasone propionate, the type and severity of adverse reactions associated with each of the compounds may be expected. There is no incidence of additional adverse events following concurrent administration of the two compounds. Adverse events which have been associated with salmeterol/fluticasone propionate are given below, listed by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (³1/100 and <1/10), uncommon (³1/1000 and <1/100), rare (³1/10,000 to <1/1000), and very rare (<1/10,000) including isolated reports. Very common, common and uncommon events were derived from clinical trial data. The incidence in placebo was not taken into account. Very rare events were derived from post-marketing spontaneous data. NOTE: The changes to this table relate purely to sequence and layout issues. There are no changes to the adverse events and/or frequency. System Organ Class Adverse Event Frequency Infections & Infestations Cardiac Disorders Candidiasis of the mouth and throat Pneumonia Bronchitis Palpitations Tachycardia Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles). Common Common1,3,5 Common1,3 Common Uncommon Very Rare Immune System Disorders Nervous System Disorders Hypersensitivity reactions with the following manifestations: Cutaneous hypersensitivity reactions Angioedema (mainly facial and oropharyngeal oedema), Respiratory symptoms (dyspnoea and/or bronchospasm), Anaphylactic reactions including anaphylactic shock Headache Tremor Uncommon Very Rare *Very Common Common Endocrine Disorders Eye Disorders Cushing’s syndrome, Cushingoid features, Adrenal suppression, Growth retardation in children and adolescents, Decreased bone mineral density Cataract, Glaucoma Very Rare4 Very Rare Metabolism & Nutrition Disorders Respiratory, Thoracic & Mediastinal Disorders Hypokalaemia Hyperglycaemia Nasopharyngitis Throat irritation Hoarseness/dysphonia Sinusitis Paradoxical bronchospasm Common3 Very Rare4 **#Very Common Common Common *#Common Very Rare Psychiatric Disorders Skin and subcutaneous tissue disorders Anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children) Contusions Very Rare *#Common Nervous System Disorders Musculoskeletal & Connective Tissue Disorders Headache Tremor Muscle cramps Traumatic fractures Arthralgia Myalgia Very Common1 Common Common *#Common Very Rare Very Rare Eye Disorders Endocrine Disorders Cataract, Glaucoma Cushing’s syndrome, Cushingoid features, Adrenal suppression, Growth retardation in children and adolescents, Decreased bone mineral density Very Rare4 Very Rare Cardiac Disorders Metabolism & Nutrition Disorders Palpitations Tachycardia Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles). Hypokalaemia Hyperglycaemia Common Uncommon Very Rare Common Very Rare Respiratory, Thoracic & Mediastinal Disorders Infections & Infestations Nasopharyngitis Throat irritation Hoarseness/dysphonia Sinusitis Paradoxical bronchospasm Candidiasis of the mouth and throat Pneumonia Bronchitis Very Common2,3 Common Common Common1,3 Very Rare4 Common *#Common *#Common Skin and subcutaneous tissue disorders Immune System Disorders Contusions Hypersensitivity reactions with the following manifestations: Cutaneous hypersensitivity reactions Angioedema (mainly facial and oropharyngeal oedema), Respiratory symptoms (dyspnoea and/or bronchospasm), Anaphylactic reactions including anaphylactic shock Common1,3 Uncommon Very Rare Musculoskeletal & Connective Tissue Disorders Psychiatric Disorders Muscle cramps Traumatic fractures Arthralgia Myalgia Anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children) Common Common1,3 Very Rare Very Rare Very Rare 1. Reported commonly in placebo 2. Reported very commonly in placebo 3. Reported over 3 years in a COPD study 4. See section 4.4 5. See section 5.1. Description of selected adverse reactions The pharmacological side effects of beta-2-agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy. Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients. Both hoarseness and incidence of candidiasis may be relieved by gargling with water after using the product. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Seretide Diskus. Pneumonia was reported in studies of patients with COPD (see section 5.1) Paediatric population Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, and growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma (see section 4.4). Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability. There have been very rare reports of hyperglycaemia (see section 4.4). As with other inhalation therapy, paradoxical broncospasm may occur (see section 4.4). 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Adrenergics and other anti-asthmatics. ATC Code: R03AK06 Seretide Asthma clinical trials A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of Seretide versus inhaled corticosteroid (Fluticasone Propionate) alone to determine whether the goals of asthma management were achievable. Treatment was stepped up every 12 weeks until **Total control was achieved or the highest dose of study drug was reached. GOAL showed more patients treated with Seretide achieved asthma control than patients treated with ICS alone and this control was attained at a lower corticosteroid dose. Well Controlled asthma was achieved more rapidly with Seretide than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual Well Controlled week was 16 days for Seretide compared to 37 days for the ICS group. In the subset of steroid naive asthmatics the time to an individual Well Controlled week was 16 days in the Seretide treatment compared to 23 days following treatment with ICS. The overall study results showed: Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC) Asthma over 12 months Pre-Study Treatment Salmeterol/FP FP WC TC WC TC No ICS (SABA alone) 78% 50% 70% 40% Low dose ICS ( ≤500mcg BDP or equivalent/day) 75% 44% 60% 28% Medium dose ICS (>500-1000mcg BDP or equivalent/day) 62% 29% 47% 16% Pooled results across the 3 treatment levels 71% 41% 59% 28% *Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung function plus no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy **Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy The results of this study suggest that Seretide 50/100mcg bd may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential (see section 4.2). A double-blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of Seretide for two weeks. The study showed that doubling the inhalations of each strength of Seretide for up to 14 days resulted in a small increase in beta-agonist-related adverse events (tremor; 1 patient [1%] vs 0, palpitations; 6 [3%] vs 1 [<1%], muscle cramps; 6[3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid related adverse events (e.g. oral candidiasis; 6 [6%] vs 16 [8%], hoarseness; 2 [2%] vs 4 [2%]) compared to one inhalation twice daily. The small increase in beta-agonist-related adverse events should be taken into account if doubling the dose of Seretide is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy. Seretide COPD clinical trials 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. Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of Seretide 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication. Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of Seretide 50/250 micrograms bd (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation. The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies. The results of both studies showed that treatment with Seretide 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured Seretide 50/250 micrograms bd over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the Seretide 50/250 micrograms bd group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with Seretide 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following treatment with Seretide 50/500 micrograms bd in TORCH. 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 (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 figures 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. Mechanism of action: Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
Treatment with Seretide should not be stopped abruptly in patients with asthma due to risk of exacerbation. Therapy should be down-titrated under physician supervision. For patients with COPD cessation of therapy may also be associated with symptomatic decompensation and should be supervised by a physician.
As with all inhaled medication containing corticosteroids, Seretide should be administered with caution in patients with pulmonary tuberculosis.
Rarely, Seretide may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. Therefore Seretide should be used with caution in patients with severe cardiovascular disorders, heart rhythm abnormalities, diabetes mellitus, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium.
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.
As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. Seretide Diskus should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
Seretide contains lactose up to 12.5 milligram /dose. This amount does not normally cause problems in lactose intolerant people.
Care should be taken when transferring patients to Seretide therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy.
The benefits of inhaled fluticasone propionate therapy should minimise the need for oral steroids, but patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time. Patients who have required high dose emergency corticosteroid therapy in the past may also be at risk. This possibility of residual impairment should always be borne in mind in emergency and elective situations likely to produce stress, and appropriate corticosteroid treatment must be considered. The extent of the adrenal impairment may require specialist advice before elective procedures.
Ritonavir can greatly increase the concentration of fluticasone propionate in plasma. Therefore, concomitant use should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects. There is also an increased risk of systemic side effects when combining fluticasone propionate with other potent CYP3A inhibitors (see section 4.5).
There was an increased reporting of lower respiratory tract infections (particularly pneumonia and bronchitis) in the TORCH study in patients with COPD receiving Seretide 50/500 micrograms bd compared with placebo as well as in studies SCO40043 and SCO100250 comparing the lower non-approved COPD dose of Seretide, 50/250 micrograms bd, to salmeterol 50 micrograms bd only (see section 4.8 and section 5.1). A similar incidence of pneumonia in the Seretide group was seen across all studies. In TORCH, older patients, patients with a lower body mass index (<25kg/m2) and patients with very severe disease (FEV1<30% predicted) were at greatest risk of developing pneumonia regardless of treatment. Physicians should remain vigilant for the possible development of pneumonia and other lower respiratory tract infections in patients with COPD as the clinical features of such infections and exacerbation frequently overlap. If a patient with severe COPD has experienced pneumonia the treatment with Seretide should be re-evaluated.
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 Seretide.
4.8 Undesirable effects
As Seretide contains salmeterol and fluticasone propionate, the type and severity of adverse reactions associated with each of the compounds may be expected. There is no incidence of additional adverse events following concurrent administration of the two compounds.
Adverse events which have been associated with salmeterol/fluticasone propionate are given below, listed by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (³1/100 and <1/10), uncommon (³1/1000 and <1/100), rare (³1/10,000 to <1/1000), and very rare (<1/10,000) including isolated reports. Very common, common and uncommon events were derived from clinical trial data. The incidence in placebo was not taken into account. Very rare events were derived from post-marketing spontaneous data.
NOTE:
The changes to this table relate purely to sequence and layout issues.
There are no changes to the adverse events and/or frequency.
System Organ Class
Adverse Event
Frequency
Infections & Infestations
Cardiac Disorders
Candidiasis of the mouth and throat
Pneumonia Bronchitis
Palpitations Tachycardia Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles).
Common
Common1,3,5
Common1,3
Common Uncommon Very Rare
Immune System Disorders
Nervous System Disorders
Hypersensitivity reactions with the following manifestations: Cutaneous hypersensitivity reactions Angioedema (mainly facial and oropharyngeal oedema), Respiratory symptoms (dyspnoea and/or bronchospasm), Anaphylactic reactions including anaphylactic shock
Headache
Tremor
Uncommon Very Rare
*Very Common Common
Endocrine Disorders
Eye Disorders
Cushing’s syndrome, Cushingoid features, Adrenal suppression, Growth retardation in children and adolescents, Decreased bone mineral density
Cataract, Glaucoma
Very Rare4
Very Rare
Metabolism & Nutrition Disorders
Respiratory, Thoracic & Mediastinal Disorders
Hypokalaemia
Hyperglycaemia
Nasopharyngitis
Throat irritation Hoarseness/dysphonia Sinusitis Paradoxical bronchospasm
Common3
**#Very Common Common Common *#Common
Psychiatric Disorders
Skin and subcutaneous tissue disorders
Anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children)
Contusions
*#Common
Musculoskeletal & Connective Tissue Disorders
Headache Tremor
Muscle cramps Traumatic fractures Arthralgia Myalgia
Very Common1 Common
Common *#Common Very Rare Very Rare
Very Common2,3 Common Common Common1,3
Common Common1,3 Very Rare Very Rare
1. Reported commonly in placebo
2. Reported very commonly in placebo
3. Reported over 3 years in a COPD study
4. See section 4.4 5. See section 5.1. Description of selected adverse reactions The pharmacological side effects of beta-2-agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy. Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients. Both hoarseness and incidence of candidiasis may be relieved by gargling with water after using the product. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Seretide Diskus. Pneumonia was reported in studies of patients with COPD (see section 5.1) Paediatric population Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, and growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma (see section 4.4). Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability. There have been very rare reports of hyperglycaemia (see section 4.4). As with other inhalation therapy, paradoxical broncospasm may occur (see section 4.4). 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Adrenergics and other anti-asthmatics. ATC Code: R03AK06 Seretide Asthma clinical trials A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of Seretide versus inhaled corticosteroid (Fluticasone Propionate) alone to determine whether the goals of asthma management were achievable. Treatment was stepped up every 12 weeks until **Total control was achieved or the highest dose of study drug was reached. GOAL showed more patients treated with Seretide achieved asthma control than patients treated with ICS alone and this control was attained at a lower corticosteroid dose. Well Controlled asthma was achieved more rapidly with Seretide than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual Well Controlled week was 16 days for Seretide compared to 37 days for the ICS group. In the subset of steroid naive asthmatics the time to an individual Well Controlled week was 16 days in the Seretide treatment compared to 23 days following treatment with ICS. The overall study results showed: Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC) Asthma over 12 months Pre-Study Treatment Salmeterol/FP FP WC TC WC TC No ICS (SABA alone) 78% 50% 70% 40% Low dose ICS ( ≤500mcg BDP or equivalent/day) 75% 44% 60% 28% Medium dose ICS (>500-1000mcg BDP or equivalent/day) 62% 29% 47% 16% Pooled results across the 3 treatment levels 71% 41% 59% 28% *Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung function plus no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy **Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy The results of this study suggest that Seretide 50/100mcg bd may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential (see section 4.2). A double-blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of Seretide for two weeks. The study showed that doubling the inhalations of each strength of Seretide for up to 14 days resulted in a small increase in beta-agonist-related adverse events (tremor; 1 patient [1%] vs 0, palpitations; 6 [3%] vs 1 [<1%], muscle cramps; 6[3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid related adverse events (e.g. oral candidiasis; 6 [6%] vs 16 [8%], hoarseness; 2 [2%] vs 4 [2%]) compared to one inhalation twice daily. The small increase in beta-agonist-related adverse events should be taken into account if doubling the dose of Seretide is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy. Seretide COPD clinical trials 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. Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of Seretide 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication. Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of Seretide 50/250 micrograms bd (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation. The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies. The results of both studies showed that treatment with Seretide 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured Seretide 50/250 micrograms bd over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the Seretide 50/250 micrograms bd group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with Seretide 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following treatment with Seretide 50/500 micrograms bd in TORCH. 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 (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 figures 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. Mechanism of action: Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
5. See section 5.1. Description of selected adverse reactions The pharmacological side effects of beta-2-agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy. Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients. Both hoarseness and incidence of candidiasis may be relieved by gargling with water after using the product. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Seretide Diskus. Pneumonia was reported in studies of patients with COPD (see section 5.1) Paediatric population Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, and growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma (see section 4.4). Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability. There have been very rare reports of hyperglycaemia (see section 4.4). As with other inhalation therapy, paradoxical broncospasm may occur (see section 4.4). 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Adrenergics and other anti-asthmatics. ATC Code: R03AK06 Seretide Asthma clinical trials A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of Seretide versus inhaled corticosteroid (Fluticasone Propionate) alone to determine whether the goals of asthma management were achievable. Treatment was stepped up every 12 weeks until **Total control was achieved or the highest dose of study drug was reached. GOAL showed more patients treated with Seretide achieved asthma control than patients treated with ICS alone and this control was attained at a lower corticosteroid dose. Well Controlled asthma was achieved more rapidly with Seretide than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual Well Controlled week was 16 days for Seretide compared to 37 days for the ICS group. In the subset of steroid naive asthmatics the time to an individual Well Controlled week was 16 days in the Seretide treatment compared to 23 days following treatment with ICS. The overall study results showed: Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC) Asthma over 12 months Pre-Study Treatment Salmeterol/FP FP WC TC WC TC No ICS (SABA alone) 78% 50% 70% 40% Low dose ICS ( ≤500mcg BDP or equivalent/day) 75% 44% 60% 28% Medium dose ICS (>500-1000mcg BDP or equivalent/day) 62% 29% 47% 16% Pooled results across the 3 treatment levels 71% 41% 59% 28% *Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung function plus no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy **Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy The results of this study suggest that Seretide 50/100mcg bd may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential (see section 4.2). A double-blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of Seretide for two weeks. The study showed that doubling the inhalations of each strength of Seretide for up to 14 days resulted in a small increase in beta-agonist-related adverse events (tremor; 1 patient [1%] vs 0, palpitations; 6 [3%] vs 1 [<1%], muscle cramps; 6[3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid related adverse events (e.g. oral candidiasis; 6 [6%] vs 16 [8%], hoarseness; 2 [2%] vs 4 [2%]) compared to one inhalation twice daily. The small increase in beta-agonist-related adverse events should be taken into account if doubling the dose of Seretide is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy. Seretide COPD clinical trials 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. Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of Seretide 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication. Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of Seretide 50/250 micrograms bd (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation. The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies. The results of both studies showed that treatment with Seretide 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured Seretide 50/250 micrograms bd over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the Seretide 50/250 micrograms bd group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with Seretide 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following treatment with Seretide 50/500 micrograms bd in TORCH. 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 (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 figures 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. Mechanism of action: Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
Description of selected adverse reactions
The pharmacological side effects of beta-2-agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.
Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients. Both hoarseness and incidence of candidiasis may be relieved by gargling with water after using the product. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Seretide Diskus.
Pneumonia was reported in studies of patients with COPD (see section 5.1) Paediatric population Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, and growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma (see section 4.4). Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability. There have been very rare reports of hyperglycaemia (see section 4.4). As with other inhalation therapy, paradoxical broncospasm may occur (see section 4.4). 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Adrenergics and other anti-asthmatics. ATC Code: R03AK06 Seretide Asthma clinical trials A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of Seretide versus inhaled corticosteroid (Fluticasone Propionate) alone to determine whether the goals of asthma management were achievable. Treatment was stepped up every 12 weeks until **Total control was achieved or the highest dose of study drug was reached. GOAL showed more patients treated with Seretide achieved asthma control than patients treated with ICS alone and this control was attained at a lower corticosteroid dose. Well Controlled asthma was achieved more rapidly with Seretide than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual Well Controlled week was 16 days for Seretide compared to 37 days for the ICS group. In the subset of steroid naive asthmatics the time to an individual Well Controlled week was 16 days in the Seretide treatment compared to 23 days following treatment with ICS. The overall study results showed: Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC) Asthma over 12 months Pre-Study Treatment Salmeterol/FP FP WC TC WC TC No ICS (SABA alone) 78% 50% 70% 40% Low dose ICS ( ≤500mcg BDP or equivalent/day) 75% 44% 60% 28% Medium dose ICS (>500-1000mcg BDP or equivalent/day) 62% 29% 47% 16% Pooled results across the 3 treatment levels 71% 41% 59% 28% *Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung function plus no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy **Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy The results of this study suggest that Seretide 50/100mcg bd may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential (see section 4.2). A double-blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of Seretide for two weeks. The study showed that doubling the inhalations of each strength of Seretide for up to 14 days resulted in a small increase in beta-agonist-related adverse events (tremor; 1 patient [1%] vs 0, palpitations; 6 [3%] vs 1 [<1%], muscle cramps; 6[3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid related adverse events (e.g. oral candidiasis; 6 [6%] vs 16 [8%], hoarseness; 2 [2%] vs 4 [2%]) compared to one inhalation twice daily. The small increase in beta-agonist-related adverse events should be taken into account if doubling the dose of Seretide is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy. Seretide COPD clinical trials 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. Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of Seretide 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication. Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of Seretide 50/250 micrograms bd (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation. The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies. The results of both studies showed that treatment with Seretide 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured Seretide 50/250 micrograms bd over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the Seretide 50/250 micrograms bd group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with Seretide 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following treatment with Seretide 50/500 micrograms bd in TORCH. 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 (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 figures 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. Mechanism of action: Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
Pneumonia was reported in studies of patients with COPD (see section 5.1)
Paediatric population Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, and growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma (see section 4.4). Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability. There have been very rare reports of hyperglycaemia (see section 4.4). As with other inhalation therapy, paradoxical broncospasm may occur (see section 4.4). 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Adrenergics and other anti-asthmatics. ATC Code: R03AK06 Seretide Asthma clinical trials A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of Seretide versus inhaled corticosteroid (Fluticasone Propionate) alone to determine whether the goals of asthma management were achievable. Treatment was stepped up every 12 weeks until **Total control was achieved or the highest dose of study drug was reached. GOAL showed more patients treated with Seretide achieved asthma control than patients treated with ICS alone and this control was attained at a lower corticosteroid dose. Well Controlled asthma was achieved more rapidly with Seretide than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual Well Controlled week was 16 days for Seretide compared to 37 days for the ICS group. In the subset of steroid naive asthmatics the time to an individual Well Controlled week was 16 days in the Seretide treatment compared to 23 days following treatment with ICS. The overall study results showed: Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC) Asthma over 12 months Pre-Study Treatment Salmeterol/FP FP WC TC WC TC No ICS (SABA alone) 78% 50% 70% 40% Low dose ICS ( ≤500mcg BDP or equivalent/day) 75% 44% 60% 28% Medium dose ICS (>500-1000mcg BDP or equivalent/day) 62% 29% 47% 16% Pooled results across the 3 treatment levels 71% 41% 59% 28% *Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung function plus no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy **Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy The results of this study suggest that Seretide 50/100mcg bd may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential (see section 4.2). A double-blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of Seretide for two weeks. The study showed that doubling the inhalations of each strength of Seretide for up to 14 days resulted in a small increase in beta-agonist-related adverse events (tremor; 1 patient [1%] vs 0, palpitations; 6 [3%] vs 1 [<1%], muscle cramps; 6[3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid related adverse events (e.g. oral candidiasis; 6 [6%] vs 16 [8%], hoarseness; 2 [2%] vs 4 [2%]) compared to one inhalation twice daily. The small increase in beta-agonist-related adverse events should be taken into account if doubling the dose of Seretide is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy. Seretide COPD clinical trials 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. Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of Seretide 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication. Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of Seretide 50/250 micrograms bd (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation. The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies. The results of both studies showed that treatment with Seretide 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured Seretide 50/250 micrograms bd over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the Seretide 50/250 micrograms bd group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with Seretide 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following treatment with Seretide 50/500 micrograms bd in TORCH. 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 (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 figures 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. Mechanism of action: Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
Paediatric population
Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, and growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma (see section 4.4). Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability. There have been very rare reports of hyperglycaemia (see section 4.4). As with other inhalation therapy, paradoxical broncospasm may occur (see section 4.4). 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Adrenergics and other anti-asthmatics. ATC Code: R03AK06 Seretide Asthma clinical trials A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of Seretide versus inhaled corticosteroid (Fluticasone Propionate) alone to determine whether the goals of asthma management were achievable. Treatment was stepped up every 12 weeks until **Total control was achieved or the highest dose of study drug was reached. GOAL showed more patients treated with Seretide achieved asthma control than patients treated with ICS alone and this control was attained at a lower corticosteroid dose. Well Controlled asthma was achieved more rapidly with Seretide than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual Well Controlled week was 16 days for Seretide compared to 37 days for the ICS group. In the subset of steroid naive asthmatics the time to an individual Well Controlled week was 16 days in the Seretide treatment compared to 23 days following treatment with ICS. The overall study results showed: Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC) Asthma over 12 months Pre-Study Treatment Salmeterol/FP FP WC TC WC TC No ICS (SABA alone) 78% 50% 70% 40% Low dose ICS ( ≤500mcg BDP or equivalent/day) 75% 44% 60% 28% Medium dose ICS (>500-1000mcg BDP or equivalent/day) 62% 29% 47% 16% Pooled results across the 3 treatment levels 71% 41% 59% 28% *Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung function plus no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy **Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy The results of this study suggest that Seretide 50/100mcg bd may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential (see section 4.2). A double-blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of Seretide for two weeks. The study showed that doubling the inhalations of each strength of Seretide for up to 14 days resulted in a small increase in beta-agonist-related adverse events (tremor; 1 patient [1%] vs 0, palpitations; 6 [3%] vs 1 [<1%], muscle cramps; 6[3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid related adverse events (e.g. oral candidiasis; 6 [6%] vs 16 [8%], hoarseness; 2 [2%] vs 4 [2%]) compared to one inhalation twice daily. The small increase in beta-agonist-related adverse events should be taken into account if doubling the dose of Seretide is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy. Seretide COPD clinical trials 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. Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of Seretide 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication. Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of Seretide 50/250 micrograms bd (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation. The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies. The results of both studies showed that treatment with Seretide 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured Seretide 50/250 micrograms bd over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the Seretide 50/250 micrograms bd group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with Seretide 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following treatment with Seretide 50/500 micrograms bd in TORCH. 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 (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 figures 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. Mechanism of action: Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, and growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma (see section 4.4). Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability.
There have been very rare reports of hyperglycaemia (see section 4.4).
As with other inhalation therapy, paradoxical broncospasm may occur (see section 4.4). 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Adrenergics and other anti-asthmatics. ATC Code: R03AK06 Seretide Asthma clinical trials A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of Seretide versus inhaled corticosteroid (Fluticasone Propionate) alone to determine whether the goals of asthma management were achievable. Treatment was stepped up every 12 weeks until **Total control was achieved or the highest dose of study drug was reached. GOAL showed more patients treated with Seretide achieved asthma control than patients treated with ICS alone and this control was attained at a lower corticosteroid dose. Well Controlled asthma was achieved more rapidly with Seretide than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual Well Controlled week was 16 days for Seretide compared to 37 days for the ICS group. In the subset of steroid naive asthmatics the time to an individual Well Controlled week was 16 days in the Seretide treatment compared to 23 days following treatment with ICS. The overall study results showed: Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC) Asthma over 12 months Pre-Study Treatment Salmeterol/FP FP WC TC WC TC No ICS (SABA alone) 78% 50% 70% 40% Low dose ICS ( ≤500mcg BDP or equivalent/day) 75% 44% 60% 28% Medium dose ICS (>500-1000mcg BDP or equivalent/day) 62% 29% 47% 16% Pooled results across the 3 treatment levels 71% 41% 59% 28% *Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung function plus no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy **Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy The results of this study suggest that Seretide 50/100mcg bd may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential (see section 4.2). A double-blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of Seretide for two weeks. The study showed that doubling the inhalations of each strength of Seretide for up to 14 days resulted in a small increase in beta-agonist-related adverse events (tremor; 1 patient [1%] vs 0, palpitations; 6 [3%] vs 1 [<1%], muscle cramps; 6[3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid related adverse events (e.g. oral candidiasis; 6 [6%] vs 16 [8%], hoarseness; 2 [2%] vs 4 [2%]) compared to one inhalation twice daily. The small increase in beta-agonist-related adverse events should be taken into account if doubling the dose of Seretide is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy. Seretide COPD clinical trials 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. Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of Seretide 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication. Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of Seretide 50/250 micrograms bd (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation. The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies. The results of both studies showed that treatment with Seretide 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured Seretide 50/250 micrograms bd over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the Seretide 50/250 micrograms bd group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with Seretide 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following treatment with Seretide 50/500 micrograms bd in TORCH. 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 (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 figures 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. Mechanism of action: Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
As with other inhalation therapy, paradoxical broncospasm may occur (see section 4.4).
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Adrenergics and other anti-asthmatics.
ATC Code: R03AK06
Seretide Asthma clinical trials
A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of Seretide versus inhaled corticosteroid (Fluticasone Propionate) alone to determine whether the goals of asthma management were achievable. Treatment was stepped up every 12 weeks until **Total control was achieved or the highest dose of study drug was reached. GOAL showed more patients treated with Seretide achieved asthma control than patients treated with ICS alone and this control was attained at a lower corticosteroid dose.
Well Controlled asthma was achieved more rapidly with Seretide than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual Well Controlled week was 16 days for Seretide compared to 37 days for the ICS group. In the subset of steroid naive asthmatics the time to an individual Well Controlled week was 16 days in the Seretide treatment compared to 23 days following treatment with ICS.
The overall study results showed:
Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC) Asthma over 12 months
Pre-Study Treatment
Salmeterol/FP
FP
WC
TC
No ICS (SABA alone)
78%
50%
70%
40%
Low dose ICS ( ≤500mcg BDP or equivalent/day)
75%
44%
60%
28%
Medium dose ICS (>500-1000mcg BDP or equivalent/day)
62%
29%
47%
16%
Pooled results across the 3 treatment levels
71%
41%
59%
*Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung function plus no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy
**Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy
The results of this study suggest that Seretide 50/100mcg bd may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential (see section 4.2).
A double-blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of Seretide for two weeks. The study showed that doubling the inhalations of each strength of Seretide for up to 14 days resulted in a small increase in beta-agonist-related adverse events (tremor; 1 patient [1%] vs 0, palpitations; 6 [3%] vs 1 [<1%], muscle cramps; 6[3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid related adverse events (e.g. oral candidiasis; 6 [6%] vs 16 [8%], hoarseness; 2 [2%] vs 4 [2%]) compared to one inhalation twice daily. The small increase in beta-agonist-related adverse events should be taken into account if doubling the dose of Seretide is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy.
Seretide COPD clinical trials
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. Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of Seretide 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication. Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of Seretide 50/250 micrograms bd (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation. The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies. The results of both studies showed that treatment with Seretide 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured Seretide 50/250 micrograms bd over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the Seretide 50/250 micrograms bd group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with Seretide 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following treatment with Seretide 50/500 micrograms bd in TORCH. 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 (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 figures 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. Mechanism of action: Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
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
0.932 (0.77, 1.13) 0.481
0.774 (0.64, 0.93) 0.007
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.
Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of Seretide 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication. Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of Seretide 50/250 micrograms bd (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation. The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies. The results of both studies showed that treatment with Seretide 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured Seretide 50/250 micrograms bd over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the Seretide 50/250 micrograms bd group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with Seretide 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following treatment with Seretide 50/500 micrograms bd in TORCH. 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 (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 figures 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. Mechanism of action: Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of Seretide 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication.
Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of Seretide 50/250 micrograms bd (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation.
The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies.
The results of both studies showed that treatment with Seretide 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured Seretide 50/250 micrograms bd over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the Seretide 50/250 micrograms bd group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with Seretide 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following treatment with Seretide 50/500 micrograms bd in TORCH.
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 (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 figures 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. Mechanism of action: Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
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 figures 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. Mechanism of action: Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
Key findings from SMART by inhaled steroid use at baseline: secondary endpoints
Number of secondary endpoint events /number of patients
Respiratory -related death
10/6127
5/6138
2.01 (0.69, 5.86)
14/7049
6/7041
2.28 (0.88, 5.94)
Combined asthma-related death or life-threatening experience
16/6127
13/6138
1.24 (0.60, 2.58)
21/7049
9/7041
2.39 (1.10, 5.22)
Asthma-related death
4/6127
3/6138
1.35 (0.30, 6.04)
9/7049
0/7041
*
(*=could not be calculated because of no events in placebo group. Risk in bold figures 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.
Mechanism of action: Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
Mechanism of action:
Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
Seretide contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below:
Salmeterol:
Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists. Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor.
Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists.
Fluticasone propionate:
Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
SUMMARY OF PRODUCT CHARACTERISTICS (changes in red)
4.5 Interaction with other medicinal products and other forms of interaction
Both non-selective and selective beta-blockers should be avoided unless there are compelling reasons for their use.
Concomitant use of other beta-adrenergic containing drugs can have a potentially additive effect.
Fluticasone Propionate
Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after inhaled dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by fluticasone propionate are unlikely.
In an interaction study in healthy subjects with intranasal fluticasone propionate, ritonavir (a highly potent cytochrome P450 3A4 inhibitor) 100 mg b.i.d. increased the fluticasone propionate plasma concentrations several hundred fold, resulting in markedly reduced serum cortisol concentrations. Information about this interaction is lacking for inhaled fluticasone propionate, but a marked increase in fluticasone propionate plasma levels is expected. Cases of Cushing’s syndrome and adrenal suppression have been reported. The combination should be avoided unless the benefit outweighs the increased risk of systemic glucocorticoid side-effects.
In a small study in healthy volunteers, the slightly less potent CYP3A inhibitor ketoconazole increased the exposure of fluticasone propionate after a single inhalation by 150%. This resulted in a greater reduction of plasma cortisol as compared with fluticasone propionate alone. Co-treatment with other potent CYP3A inhibitors, such as itraconazole, is also expected to increase the systemic fluticasone propionate exposure and the risk of systemic side-effects. Caution is recommended and long-term treatment with such drugs should if possible be avoided.
Salmeterol
Potent CYP3A4 inhibitors
Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 mcg 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 (500mg orally three times a day) and salmeterol (50mcg 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.
SUMMARY OF CHANGES TO SPC (Changes in Red)
.
There was an increased reporting of lower respiratory tract infections (particularly pneumonia and bronchitis) in the TORCH study in patients with COPD receiving Seretide compared with placebo (see section 4.8 and 5.1). In TORCH, older patients, patients with a lower body mass index (<25kg/m2) and patients with very severe disease (FEV1<30% predicted) were at greatest risk of developing pneumonia regardless of treatment. Physicians should remain vigilant for the possible development of pneumonia and other lower respiratory tract infections in patients with COPD as the clinical features of such infections and exacerbation frequently overlap. If a patient with severe COPD has experienced pneumonia the treatment with Seretide should be re-evaluated.
.etc
Adverse events which have been associated with salmeterol/fluticasone propionate are given below, listed 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 to <1/1000), and very rare (<1/10,000) including isolated reports. Very common, common and uncommon events were derived from clinical trial data. The incidence in placebo was not taken into account. Very rare events were derived from post-marketing spontaneous data.
Cataract & Glaucoma have been removed from Endocrine Disorders and moved to Eye Disorders, a new classification. In addition the order in which the System Order Classifications appear in the table below has been rearranged slightly, however there have been no changes made to the actual Adverse Events or the Frequency.
PalpitationsTachycardiaCardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles).
CommonUncommonVery Rare
HeadacheTremor
*Very CommonCommon
NasopharyngitisThroat irritationHoarseness/dysphoniaSinusitisParadoxical bronchospasm
**#Very CommonCommonCommon*#Common
Muscle crampsTraumatic fracturesArthralgiaMyalgia
Common*#CommonVery RareVery Rare
Cushings syndrome, Cushingoid features, Adrenal suppression, Growth retardation in children and adolescents, Decreased bone mineral density.
#Common
PneumoniaBronchitis
Hypersensitivity reactions with the following manifestations:Cutaneous hypersensitivity reactionsAngioedema (mainly facial and oropharyngeal oedema), Respiratory symptoms (dyspnoea and/or bronchospasm), Anaphylactic reactions including anaphylactic shock
UncommonVery Rare
*Reported commonly in placebo
**Reported very commonly in placebo
#Reported over 3 years in a COPD study
Typo changes
5.2 Pharmacokinetic properties
Changed from “The absolute bioavailability of a single dose of inhaled fluticasone propionate in healthy subjects varies between approximately 5-11% of the nominal dose depending on the inhalation device used.
To “The absolute bioavailability of a single dose of inhaled fluticasone propionate in healthy subjects varies between approximately 10-30% of the nominal dose depending on the inhalation device used