For the use only of registered medical practitioners or a hospital or a laboratory
SERETIDE TM ACCUHALERTM
Salmeterol and Fluticasone Propionate Accuhaler
COMPOSITION
Moulded plastic device containing a full strip with 60 regularly placed blisters.
Each pre-metered unit (blister) contains powder for inhalation providing Salmeterol Xinafoate IP equivalent to 50 mcg. Salmeterol and 100 mcg Fluticasone Propionate IP
Each pre-metered unit (blister) contains powder for inhalation providing Salmeterol Xinafoate IP equivalent to 50 mcg. Salmeterol and 250 mcg Fluticasone Propionate IP
Each pre-metered unit (blister) contains powder for inhalation providing Salmeterol Xinafoate IP equivalent to 50 mcg. Salmeterol and 500 mcg Fluticasone Propionate IP
PHARMACEUTICAL FORM:
Inhalation powder.
THERAPEUTIC INDICATIONS
Patients who are symptomatic on current inhaled corticosteroids therapy.
Patients on regular bronchodilator therapy who require inhaled corticosteroids.
SERETIDE is indicated for the regular treatment of Chronic Obstructive Pulmonary Disease (CDPD) including chronic bronchitis.
DOSAGE AND METHOD OF ADMINISTRATION:
SERETIDE Accuhaler is for inhalation only.
Patients should be made aware that SERETIDE Accuhaler must be used regular for optimum benefit, even when asymptomatic.
Patients should be regularly reassessed by a doctor, so that the strength of SERETIDE they are receiving remains optimal and is only changed on medical advice.
Bronchial Asthma:
The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. Where the control of symptoms is maintained with twice daily SERETIDE, titration to the lowest effective dose could include SERETIDE given once daily.
Patients should be given the strength of SERETIDE containing the appropriate Fluticasone propionate dosage for the severity of their disease.
If a patient is inadequately controlled on inhaled corticosteroid therapy alone, substitution with SERETIDE at a therapeutically equivalent corticosteroid dose may result in an improvement in asthma control. For patients whose asthma control is acceptable on inhaled corticosteroid therapy alone, substitution with SERETIDE may permit a reduction in corticosteroid dose while maintaining asthma control. For further information, please refer to the Pharmacodynamics' section.
Recommended Doses:
Adults and adolescents 12 years and older:
One inhalation (50mcg Salmeterol and 100mcg Fluticasone) twice daily.
OR
One inhalation (50mcg Salmeterol and 250mcg Fluticasone propionate) twice daily.
OR
One inhalation (50mcg Salmeterol and 500 mcg Fluticasone propionate) twice daily.
Adults 18 years and older:
Doubling the dose of all strengths of SERETIDE in adults for up to 14 days has comparable safety and tolerability to regular twice dosing and may be considered when patients require additional short term (up to 14 days) inhaled corticosteroid therapy as outlined in asthma treatment guidelines.
Children 4 years and older:
One inhalation (50 mcg Salmeterol and 100 mcg Fluticasone propionate) twice daily. There are no data available for use of SERETIDE in children aged under 4 years.
Chronic Obstruction Pulmonary Disease (COPD):
For adult patients the recommended dose is one inhalation 50/250 mcg to 50/500 mcg Salmeterol/Fluticasone propionate twice daily.
Special patient groups:
There is no need to adjust the dose in elderly patients or in those with renal or hepatic impairment.
Contraindications:
SERETIDE is contraindicated in patients with a history of hypersensitivity to any of the ingredients (see List of Excipients).
Special Warnings and Special Precautions for use:
The management of reversible obstructive airways disease should normally follow a stepwise programme and patient response should be monitored clinically and by lung function tests. SERETIDE Accuhaler is not for relief of acute symptoms for which a fast and short-acting bronchodilator (e.g. salbutamol) is required. Patients should be advised to have their relief medication available at all times. 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 be reviewed by a physician. Consideration should be given to increasing corticosteroid therapy. Also, where the current dosage of SERETIDE has failed to give adequate control of reversible obstructive airways disease, the patient should be reviewed by a physician.
For patient with asthma or COPD, consideration should be given to additional corticosteroid therapies and administration of antibiotics if an exacerbation is associated with infection.
Treatment with SERETIDE should not be stopped abruptly in patients with asthma due to risk of exacerbation; therapy should be titrated-down under physician supervision. For patients with COPD, cessation of therapy may be associated with symptomatic decompensation and should be supervised by a physician.
There was an increase reporting of pneumonia in studies of patient with COPD receiving SERETIDE (see ADVERSE REACTIONS). Physician should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbation frequently overlap.
As with all inhaled medication containing corticosteroid, SERETIDE should be administered with caution in patients with active or quiescent pulmonary tuberculosis. SERETIDE should be administered with caution in patients with thyrotoxicosis. Cardiovascular effect such as increases in systolic blood pressure and heart rate, may occasionally be seen with all sympathomimetic drugs, especially at higher than therapeutic doses. For this reason, SERETIDE should be used with caution in patients with pre-existing cardiovascular disease. A transient decrease in serum potassium may occur with all sympathomimetic drugs at higher therapeutic dose. Therefore, SERETIDE should be used with caution in patients predisposed to low levels serum potassium. Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods; these effects are much alike to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, cushingoid features, and adrenal suppression, growth degradation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important, therefore for reversible obstructive airways disease patients that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control is maintained.
There have been rare reports of increases in blood glucose levels (see undesirable effects) and this should be considered when prescribing to patients with a history of diabetes mellitus. During post-marketing use there have been reports of clinically significant drug interactions in patients receiving Fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of Fluticasone propionate and ritonavir should be avoided. Unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects (see Interactions with Other Medicinal Products and Others Forms of Interaction).
Data from a large US study (SMART) comparing the safety of salmeterol (a component of SERETIDE) or placebo added to usual therapy showed a significant increase in asthma-related deaths in patients receiving salmeterol. Data from the study suggested that African-American patients may be at greater risk of serious respiratory -related events or deaths when using salmeterol compared to placebo. It is not known if this was due to pharmacogenetic or other factors. The SMART study was not designed to determine whether concurrent use of inhaled corticosteroid modifies the risk of asthma-related death. (see clinical studies). It was observed in a drug interaction study that concomitant use of systemic ketoconazole increases exposure to salmeterol. This may lead to prolongation in the QTc interval. Caution should be exercised when strong CYP2A4 inhibitors (e.g. ketoconazole) are co-administered with salmeterol (Interactions with Other Medicinal Products and Others Forms of Interaction).
and pharmacokinetic properties).
Interactions with Other Medicinal Products and Others Forms of Interaction):
Both non-selective and selective beta-blockers should be avoided unless there are compelling reasons for their use. 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 in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can greatly increase Fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations. During post marketing use, there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled Fluticasone propionate and ritonavir resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of Fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Studies have shown that other inhibitors of cytochrome P450 3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to Fluticasone propionate without notable reductions in serum cortisol concentrations. Nevertheless, care is advised when co-administering potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole) as there is potential for increased systemic exposure to Fluticasone propionate. Co-administration of ketoconazole and salmeterol resulted in a significant increase in plasma salmeterol exposure (1.4- fold Cmax and 15-fold AUC) and this may cause a prolongation of the QTc interval (see Special Warnings and Special Precautions For Use and Pharmacokinetic Properties)
PREGNANCY AND LACTATION:
Administration of drugs during pregnancy and lactation should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus or child. There is sufficient experience of the use of salmeterol Xinafoate and Fluticasone propionate in human pregnancy and lactation. Reproductive toxicity studies in animals either with single drug or in combination revealed the foetal effects expected at extensive systemic exposure levels of a potent beta 2 adrenoreceptor agonist and glucocorticosteroid. Extensive clinical experience with drugs in these classes has revealed no evidence that the effects are relevant at therapeutic doses. Neither salmeterol Xinafoate nor Fluticasone propionate has shown any potential for generic toxicity.
Salmeterol and Fluticasone propionate concentration in plasma after inhaled therapeutic doses are very low and therefore concentrations in human breast milk are likely to be correspondingly low. This is supported by studies in lactating animals in which low drug concentrations were measured in milk. There are no data available for human breast milk.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
There have been no specific studies of the effect of SERETIDE on the above activities but the pharmacology of both drugs does not indicate any effect.
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.
As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a fast and short-acting inhaled bronchodilator. Salmeterol/Fluticasone propionate Accuhaler should be discontinued immediately, the patient assessed and alterative therapy instituted if necessary. Adverse events which have been associated with salmeterol or Fluticasone propionate are given below.
Salmeterol:
The pharmacological side effects of beta 2 agonist treatments, such as tremor, subjective palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy. Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extra systoles) may occur, usually in susceptible patients. There have been very rare reports of arthralgia. Hypersensitivity reactions, including anaphylactic reactions such as oedema and angioedema, bronchospasm and anaphylactic shock have been reported very rarely. There have also been uncommon reports of rash. There have been reports of oropharyngeal irritation, muscle cramps, hyperglycemia.
Fluticasone propionate:
Hoarseness and candidates (thrush) of the mouth and throat can occur in some patients. There have been uncommon reports of cutaneous hypersensitivity reactions. There have also been rarely reports of hypersensitivity reactions manifesting angioedema (mainly facial and oropharyngeal oedema) respiratory symptoms (dyspnoea and/or bronchospasm) and very rarely, anaphylactic reactions. Both hoarseness and incidence of candidiasis may be relieved by gargling with water after use of salmeterol /Fluticasone propionate Accuhaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with salmeterol/Fluticasone propionate Accuhaler.
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 (see Special Warnings and Special Precautions for Use.) there have been very rare reports of hyperglycemia, anxiety, sleep disorders and behavioral changes, including hyperactively and irritability (predominantly in children).
Salmeterol/Fluticasone propionate clinical trails:
There have been uncommon reports of contusions. The following undesirable effects were commonly reported: Hoarseness/dysphonia, throat irritation, headache, candidiasis of mouth and throat and palpitations. Pneumonia (in COPD patients).
Salmeterol/Fluticasone post marketing:
There have been uncommon reports of cutaneous hypersensitivity reactions. There have also been rare reports of hypersensitivity reactions manifesting as angioedema (mainly facial and oropharyngeal oedema, respiratory symptoms (dyspnea and/or bronchospasm) and very rarely, anaphylactic reactions. There have been very rare reports of anxiety, sleep disorders and behavioral changes, including hyperactivity and irritability (predominantly in children). There have also been very rare reports of hyperglycemia.
OVERDOSE:
The available information on overdose with SERETIDE salmeterol and/or Fluticasone propionate is given below:
The expected symptoms and signs of salmeterol overdosage are those typically of excessive beta 2 adrenergic stimulation, including tremor, headache, tachycardia, increases in systolic blood pressure and hypokalemia.
Acute inhalation of Fluticasone propionate doses in excess of those approved may lead to temporary suppression of the hypothalamic-pituitary-adrenal axis. This does not usually require emergency action as normal adrenal function typically recovers within a few days.
If higher than approved doses of SERETIDE are continued over prolonged periods, significant adrenocortical suppression is possible. There have been very rare reports of acute adrenal crisis, mainly occurring in children exposed to higher than approved doses over prolonged periods (several months or years); observed features have included hypoglycemia associated with decreased consciousness and/or convulsions. Situation which could potentially trigger acute adrenal crisis include exposure to trauma, surgery, infection or any rapid reduction in the dosage of the inhaled Fluticasone propionate component. It is not recommended that patients receive higher than approved doses of SERETIDE. It is important to review therapy regularly and titrate down to the lowest approved dose at which effective control of disease is maintained.
PHARMACODYNAMIC PROPERTIES:
Salmeterol clinical trials
Asthma
The salmeterol multi-center asthma research trial (SMART) was a large US study that compared the safety of salmeterol or placebo added to usual therapy. There were no significant differences in the primary endpoint of the combined number of respiratory-related life-threatening experiences. The study showed a significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13, 176 patients treated was no significant difference between treatment groups for asthma-related deaths for those patients using inhaled steroids at baseline (4/5127 on salmeterol versus 3/6138 on placebo). The numbers of asthma-related deaths in the groups not using inhaled steroids were 9/7049 on salmeterol versus 0/7041 on placebo. Further a meta-analysis of 42 clinical studies involving 8,030 patients on SERETIDE and 7,925 patients on Fluticasone propionate did not show a statistical difference between SERETIDE and Fluticasone propionate for serious respiratory related events or asthma-related hospitalizations.
SERETIDE clinical trials
Asthma
A large twelve-month study (Gaining Optimal Asthma Control, GOAL) in 3416 asthma patients compared the efficacy and safety of SERETIDE versus inhaled corticosteroid alone in achieving pre-defined levels of asthma control. Treatment was stepped-up every 12 weeks until ** total control was achieved or the highest does of study drug was reached. Control needed to be sustained for at least 7 out of the last 8 weeks of treatment. The study showed that:
These effects were observed earlier with SERETIDE compared with inhaled corticosteroid with inhaled corticosteroid alone and at a lower inhaled corticosteroid dose.
The GOAL study also showed that:
{*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.} Two further studies have shown improvements in ling function,, percentage of symptoms free days and reduction in rescue medication use, at 60% lower inhaled corticosteroid dose with SERETIDE compared to treatment with inhaled corticosteroid alone, whilst the control of the underlying airway inflammation, measured by bronchial biopsy and bronchoalveolar lavage, was maintained.
Additional studies have shown that treatment with SERETIDE significantly improves asthma symptoms, lung function and reduces the use of rescue medication compared to treatment with the individual components alone and placebo. Results from GOAL show that the improvements seen with SERETIDE, in these endpoints, are maintained over at least 12 months.
COPD
Symptomatic COPD patients without restriction to 10% reversibility to a short acting beta 2 agonist:
Placebo-controlled clinical trials, over 6 months, have shown that regular use of SERETIDE 50/250 and 50/500 micrograms rapidly and significantly improves lung function, significantly reduced breathlessness and the use of relief medication. There were also significant improvements in health status.
Symptomatic COPD patients who demonstrated less than 10% reversibility to a short beta 2-agonist:-
Placebo-controlled clinical trials over 6 and 12 months, have shown that regular use of SERETIDE 50/500 micrograms rapidly and significantly improves lung function, significantly reduced breathlessness and the use of relief medication. Over a 12-month period the risk of COPD exacerbations and the need for additional courses of oral corticosteroids was significantly reduced. There were also significantly improvements in health status. SERETIDE 50/500 micrograms was effective in improving lung function, health status and reducing the risk of COPD exacerbations, in both current and ex-smokers.
TORCH study towards a revolution in COPD Health:
TORCH was a 3 year study to assess the effect of treatment with SERETIDE Accuhaler/ Diskus 50/500 micrograms twice daily, salmeterol Accuhaler/Diskus 50 micrograms twice daily, FP Accuhaler/Diskus 500 micrograms twice daily or placebo on all cause mortality in patients with COPD. Patients with moderate to severe COPD with a baseline (pre-bronchodilator) FEV1 <60% of predicted normal were randomized to double-blind medication. During 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 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 |
SERETIDE reduced the risk of dying at any time during the 3 years by 17.5% compared to placebo (Hazard ratio 0.825 (95% CL 0.68, 1.00, 0=0.052; all adjusted for interim analyses). There was a 12% reduction in the risk of dying at anytime within 3 years from any cause for salmeterol compared with placebo (p=0.180) and a 6% increase for FP compared with placebo (p=0.525). a supporting analysis using Cox's Proportional Hazards model gave a hazard ratio of 0.811 (95% CL 0.670, 0.982, p=0.031) for SERETIDE vs placebo which represented a 19% reduction in the risk of dying at any time within 3 years. The model adjusted for important factors (smoking status, age, sex, region, baseline FEV1 and body mass index). There was no evidence that treatment effects varied for these factors. 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. SERETIDE reduced the rate of moderate to severe exacerbations by 25% (95% Cl; 19% Cl to 31%, p<0.001) compared with placebo. SERETIDE reduced the exacerbation rate by 12% compared with salmeterol (95% Cl; 5% to 19%, p=0.002) and 9% compared with FP (95% Cl; 1% to 16% , p= 0.024). Salmeterol and FP significantly reduced rates compared with placebo by 15% (95% Cl; 7% to 22%; p<0.001) and 18% (95% Cl; 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% Cl- 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). Over the 3 years treatment period FEV1 values were higher in subjects treated with SERETIDE than for those treated with placebo (average difference over 3 years 92ml 95% Cl; 75 to 108 mL; p<0.001). SERETIDE was also more effective than salmeterol or FP in improving FEV1 (average difference 50ml, p< 0.001 for salmeterol and 44ml, p< 0.001 for FP). The estimated 3 years 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 of SERETIDE vs placebo: 164, 95% Cl: 1.33 to 2.01; p<0.001). There was no increase in pneumonia related deaths; deaths on treatment that were adjustment 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% plcabo, 5.1% salmeterol, 5.4 FP and 6.3% SERETIDE). Hazards ration for SERETIDE vs placebo; 1.22, 95% Cl; 0.87 to 1.72, p=0.240). The incidence of adverse events of eye disorders, bone disorders, and HPA axis disorders was low and there was no difference observed between treatments. There was no evidence of an increase in cardiac adverse events in the treatment groups receiving salmeterol.
Mechanism of Action:
SERETIDE contains salmeterol and Fluticasone propionate which have models of action. Salmeterol products against symptoms Fluticasone propionate improves lung function and events exacerbations of the condition. SERETIDE offered more convenient regime for patients on concurrent beta-agonist and inhaled corticosteroid therapy. The respective mechanism of action of both drugs are discussed below:
Salmeterol:-
Salmeterol is a selective long-acting (12hours) beta 2 adrenoceptor agonist with a long side chain which binds to the other site of the receptor. These pharmacological properties of salmeterol offer more effective protection against histamine-induced bronchoconstriction of produce longer duration of bronchodilator, lasting for at least 12 hours than cases of conventional short-acting beta2 agonists.
In vitro tests have shown salmeterol is a potent and long-lasting inhibitor from human lung, or mass cell mediators such as histamine, prostaglandin. In man salmeterol inhibits the early and late phase response to inhaled allergen; the latter persisting for over 30 hours after a single dose when the bronchodilator effect is no longer evident. Single dosing with salmeterol attenuates bronchial hyper-responsive. These properties indicate that salmeterol has additional non-bronchodilator activity but the full clinical significance is not yet clear. This mechanism is different from the anti-inflammatory effect of corticosteroids.
Fluticasone Propionate:
Fluticasone propionate given by inhalation at recommended doses has a potent glucocorticoid anti-inflammation action within the lungs resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically. Daily output of adrenocortical hormones usually remain within the normal range during chronic treatment with inhaled Fluticasone propionate, even at the higher recommended doses in children and adults. After transfer from other inhaled steroids, the daily output gradually improves despite past and present intermittent use of oral steroids, thus demonstrating return of normal adrenal function on inhaled Fluticasone propionate. The adrenal reserve also remains normal during chronic treatment, as measured by a normal increment on a stimulation test. However, any residual impairment of adrenal function on inhaled Fluticasone propionate. The adrenal reserve also remains normal during chronic treatment, as measured increment on a stimulation test. However, any residual impairment of adrenal reserve from previous treatment may persist for a considerable time and should be brone in mind (see Special Warnings and Special Precautions for Use).
PHARMACOKINETICS PROPERTIES:
There is no evidence in animal or human subjects that the administration of salmeterol and Fluticasone propionate together by the inhaled route affects the pharmacokinetics of either component. For pharmacokinetic purposes therefore each component can be considered separately. In a placebo-controlled, crossover drug interaction study in 15 healthy subjects, co-administration of salmeterol (50 mcg twice daily inhaled) and the CYP3A4 inhibitor ketoconazole (400mcg once daily orally) for 7 days resulted in a significant increase in plasma salmeterol exposure. (1.4-fold Cmax and 15-fold AUC). There was no increase in salmeterol accumulation with repeat dosing. Three subjects were withdrawn from salmeterol and ketoconazole co-administration due to QTc prolongation or palpitations with sinus tachycardia. In the remaining 12 subjects, co-administration of salmeterol and ketoconazole did not result in a clinically significant effect on heart rate, blood potassium or QTc duration (see Special Warnings and Precautions For Use* and *Interaction with other medicinal products and other forms of interactions*).
Salmeterol:
Salmeterol acts locally in the lung therefore plasma levels are not an indication of therapeutic effects. In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma due to the low plasma concentrations at therapeutic doses (approximately 200 pg/ml or less) achieved after inhaled dosing. After regular dosing with salmeterol Xinafoate, hydroxynaphthoic acid can be detected in the systemic circulation, reaching steady state concentrations of approximately 100ng/ml. These concentrations are up to 1000 fold lower than steady state levels observed in toxicity studies. No detrimental effects have been seen following long-term regular dosing (more than 12 months) in patients with airway obstruction. An in vitro study showed no clinically significant changes in Pharmacodynamic effects at 500 mg three times daily doses of erythromycin. However, a salmeterol-ketoconazole interaction study resulted in a significant increase in plasma salmeterol exposure. (see Special warnings and precautions for use and interaction with other medicinal products and other forms of interactions)
Fluticasone propionate:
The absolute bioavailability of Fluticasone propionate for each of the available inhaler devices has been estimated from within and between study comparisons of inhaled and intravenous pharmacokinetic data. In healthy adult subjects the absolute bioavailability has been estimated for Fluticasone propionate Accuhaler/Diskus (7.8%), Fluticasone propionate Evohaler (10.9%), salmeterol-fluticasone propionate Evohaler (5.3%) and salmeterol-fluticasone propionate Accuhaler/Diskus (5.5%) respectively.
In patients with asthma or COPD a lesser degree of systemic exposure to inhaled Fluticasone propionate has been observed. Systemic absorption occurs mainly through the lungs and is initially rapid than prolonged. The remainder of the inhaled dose may be swallowed but contributes minimally to systemic exposure due to the low aqueous solubility and pre-systemic metabolism, resulting in oral availability of less than 1%. There is a linear increase in systemic exposure with increasing inhaled dose. The disposition of Fluticasone propionate is characterized by high plasma clearance (1150 ml/min), a large volume of distribution at steady state (approximately 300 l) and a terminal half-life of approximately 8 hours. Plasma protein binding is moderately high (91%). Fluticasone propionate is cleared very rapidly from the systemic circulation, principally by metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. The renal clearance of Fluticasone propionate is negligible (<0.2%) and less than 5% as the metabolite. Care should be taken when co-administering known CYP3A4 inhibitions, as there is potential for increased systemic exposure to Fluticasone propionate.
Special Patient Populations :
- Higher FP exposure seen flowing administration of SERETIDE (50/100 micrograms) compared to FP alone (100 mcg) in adolescents and adults (ratio 1.52 (90%Cl 1.08, 2.13) and children (ratio 1.20 909% Cl 1.06, 1.37)).
- Higher FP exposure observed in children taking SERETIDE (50/100 mcg) compared to adolescents and adults (ratio 1.63) (90% Cl 1.35, 1.96)).
- The clinical relevance of these findings are not known, however no differences in HPA axis effects were observed in clinical studies of up to 12 weeks duration comprising SERETIDE (50/100 mcg) and FP (100 mcg) in both adolescents and adults and in children.
- FP exposure was similar at the higher SERETIDE 50/500 mcg dose compared to equivalent FP dose alone.
- Higher salmeterol exposure was observed in children taking SERETIDE (50/100mcg) compared to adolescents and adults (ratio 1.23 (90% Cl 1.10, 1.38)).
- The clinical relevance of these findings are not known, however there were no differences observed in cardiovascular effects or reports of tremor between adults, adolescents and children in clinical studies of up to 12 weeks durations.
PRECLINICAL SAFETY DATA:
Salmeterol Xinafoate and Fluticasone propionate have been extensively evaluated in animal toxicities occurred only at doses in excess of those recommended for human use and were those expected for a patient Beta 2 adrenoreceptor agonist and glucocorticosteroid. In long-term studies, salmeterol Xinafoate induced benign tumours of smooth muscle in the mesovarium of rats and uterus of mice. Rodents are sensitive to the formation of these pharmacologically- induced tumours. Salmeterol is not considered to represent a significant oncogenic hazard to man. Co-administration of salmeterol and Fluticasone propionate resulted in some cardiovascular interactions at high doses. In rats, mild atrial myocarditis and focal coronary arteritis were transient effects that resolved with regular dosing. In dogs, heart rate increases were greater after co-administration than after salmeterol alone. No clinically relevant serious adverse cardiac effects have been observed in studies in man. Co-administration did not modify other class-related toxicities in animals.
LIST OF EXCIPIENTS:
Lactose (which contains milk protein)
INCOMPATIBITIES:
None reported.
SHELF-LIFE:
18 months
SPECIAL PRECAUTIONS FOR STORAGE :
Store protected from moisture, at temperature not exceeding 30 degrees C.
INSTRUCTIONS FOR USE/ HANDLING:
The Accuhaler releases a powder which is inhaled into drugs. The device is opened and primed by sliding the lever. The mouthpiece is then placed in the mouth and the tips closed around it. The dose can then be inhaled and the device closed. A dose indicator on the Accuhaler indicates the number of doses left.
Instruction for use of your SERETIDE Accuhaler
Closed
When you take your Accuhaler out of its box, it will be in the closed position.
Opened :
A new Accuhaler contains 60 doses individually protected doses of your medicine, in powder form. The dose indicator tells you how many doses are left.
Each dose is accurately measured and hygienically protected. It requires no maintenance-and no refilling. The dose indicator on top of your Accuhaler tells you how many doses are left. Numbers 5 to 0 will appear in RED, to warn you when there are only a few doses left.
The Accuhaler is easy to use. When you need a dose, just follow the four simple steps illustrated:-
How your Accuhaler works:
Sliding the lever of your Accuhaler opens a small hole in the mouthpiece and unwraps a dose, ready for you to inhale it. When you close the Accuhaler, the lever automatically moves back to its original position, ready for your next dose when you need it. The outer case protects your Accuhaler when it is not in use.
How to use the Accuhaler:
To open your Accuhaler, hold the outer case in one hand and put the thumb of your other hand on the thumb grip. Push your thumb away from you as far as it will go.
Hold your Accuhaler with the mouthpiece towards you. Slide the lever away from you, as far as it will go- until it clicks. Your Accuhaler is now ready to use. Every time the lever is pushed back, a dose is made available for inhaling. This is shown by the dose counter. Do not play with the lever as this releases doses which will be wasted.
- Before you start to inhale the dose, read through this section carefully.
- Hold the Accuhaler away from your mouth. Breathe out as far as is comfortable. Remember- never breathe into your Accuhaler.
- Put the mouthpiece to your lips. Breathe in steadily and deeply- through the Accuhaler, not through your nose.
- Remove the Accuhaler from your mouth.
- Hold your breath for about 10 seconds, or for as long as is comfortable.
- Breathe out slowly
To close your Accuhaler, put your thumb in the thumbgrip, and slide the thumbgrip back towards you, as far as it will go.
When you close the Accuhaler, it clicks shut. The lever automatically returns to its original position and is reset. Your Accuhaler is now ready for you to use again.
If you have been instructed to take two inhalations you must close the Accuhaler and repeat stages 1 to 4.
REMEMBER
Keep your Accuhaler dry.
Keep it closed when not in use.
Never breathe into your Accuhaler
Only slide the lever when you are ready to take a dose.
Do not exceed the stated dose.
Keep away from children.
Manufactures by:
Glaxo Operations UK Ltd
Priory Street, Ware,
Hertfordshire, SG12 ODJ, UK
Imported by:
GlaxoSmithKline Pharmaceuticals Ltd,
S. No. 14/4, Godown No 1 & 2
Village Yavai
Dist. Thane, Bhiwandi.
Marketed by:
GlaxoSmithKline Pharmaceuticals Limited
Dr. Annie Besant Road, Mumbai 400 030, India.
Seretide and Accuhaler are Trade Marks of GlaxoSmithKline Group of Companies.