Seretide Diskus

/ GSK

Asthma:  Adults & adolescents 12 years & older: One inhalation of 50 micrograms salmeterol and 100 micrograms fluticasone propionate twice daily. or – One inhalation of 50 micrograms salmeterol and 250 micrograms fluticasone propionate twice daily. or – One inhalation of 50 micrograms salmeterol and500 micrograms fluticasone propionate twice daily. A short term trial of Seretide may be considered as initial maintenance therapy in adults or adolescents with moderate persistent asthma (defined as patients with daily symptoms, daily rescue use and moderate to severe airflow limitation) for whom rapid control of asthma is essential. In these cases, the recommended initial dose is one inhalation of 50 micrograms salmeterol and 100 micrograms fluticasone propionate twice daily. Once control of asthma is attained treatment should be reviewed and consideration given as to whether patients should be stepped down to an inhaled corticosteroid alone. Regular review of patients as treatment is stepped down is important. A clear benefit has not been shown as compared to inhaled fluticasone propionate alone used as initial maintenance therapy when one or two of the criteria of severity are missing. In general inhaled corticosteroids remain the first line treatment for most patients. Seretide is not intended for the initial management of mild asthma. Seretide 50 microgram/100 micrograms strength is not appropriate in adults and children with severe asthma; it is recommended to establish the appropriate dosage of inhaled corticosteroid before any fixed combination can be used in patients with severe asthma.
Children 4 years & older: One inhalation of 50 micrograms salmeterol and 100 micrograms fluticasone propionate twice daily. The maximum licensed dose of fluticasone propionate delivered by Seretide Diskus in children is 100 mcg twice daily. There are no data available for use of Seretide in children aged under 4 years.
COPD:  Adults: One inhalation of 50 micrograms salmeterol and 250 micrograms fluticasone propionate twice daily. or – One inhalation of 50 micrograms salmeterol and 500 micrograms fluticasone propionate twice daily.
Special patient groups: There is no need to adjust the dose in elderly patients or in those with renal impairment. There are no data available for use of Seretide in patients with hepatic impairment.
Using the Diskus: The device is opened and primed by sliding the lever. The mouthpiece is then placed in the mouth and the lips closed round it. The dose can then be inhaled and the device closed.

Regular treatment of severe and moderate reversible obstructive airways disease (ROAD), including asthma in children and adults, where use of a combination (bronchodilator and inhaled corticosteroid) has been found to be appropriate. Symptomatic treatment of patients with severe COPD FEV1<50% predicted normal and a history of repeated exacerbations, who have significant symptoms despite regular bronchodilator therapy.

Seretide is contraindicated in patients with hypersensitivity (allergy) to any of the active substances or to the excipient.

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. 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. For patients with COPD experiencing exacerbations, treatment with systemic corticosteroids is typically indicated, therefore patients should be instructed to seek medical attention if symptoms deteriorate with Seretide. 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  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. 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, decrease in bone mineral density, cataract and glaucoma and more rarely, a range of psychological or behavioral effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). 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. Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of fluticasone propionate between 500 and less than 1000 micrograms. 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. 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 compared with placebo as well as in studies SCO40043 and SCO1000250 comparing the lower nonapproved COPD dose of Seretide, 50/250 micrograms bd, to salmeterol 50 micrograms bd only. 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 (<25 kg/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. 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.
Paediatric population: Children and adolescents <16years taking high doses of fluticasone propionate (typically ≥ 1000 micrograms/day) may be at particular risk of systemic effects. 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 and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression. 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.

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.
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 antifungal therapy whilst still continuing with the Seretide Diskus.
Paediatric population: Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression and growth retardation in children and adolescents. Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability.
For full details see prescribing information.

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 micrograms inhaled twice daily) in 15 healthy subjects for 7 days resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC). This may lead to an increase in the incidence of other systemic effects of salmeterol treatment (e.g. prolongation of QTc interval and palpitations) compared with salmeterol or ketoconazole treatment alone. 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 (50 micrograms inhaled twice daily) in 15 healthy subjects for 6 days resulted in a small but non-statistically significant increase in salmeterol exposure (1.4-fold Cmax and 1.2-fold AUC). Co-administration with erythromycin was not associated with any serious adverse effects.

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. 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: 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 breastfeeding for the child and the benefit of therapy for the woman.

The available information on overdose with salmeterol-FP, salmeterol and/or fluticasone propionate is given below: It is not recommended that patients receive higher than approved doses of salmeterol-FP. It is important to review therapy regularly and titrate down to the lowest approved dose at which effective control of disease is maintained.
Symptoms and Signs: The expected signs and symptoms of salmeterol overdose are those typical of excessive beta2–adrenergic stimulation including tremor, headache and tachycardia, increases in systolic blood pressure and hypokalaemia. 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 adrenal function typically recovers within a few days. If higher than approved dosage is 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 hypoglycaemia associated with decreased consciousness and/or convulsions. Situations 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.
Treatment: The preferred antidotes for salmeterol overdose are cardioselective beta-blocking agents, which should be used with caution in patients with a history of bronchospasm. If Salmeterol-FPtherapy has to be withdrawn due to overdose of the beta agonist component of the drug, provision of appropriate replacement steroid therapy should be considered.
For full information see prescribing information.