Full Prescribing Info
Contents
Salmeterol xinafoate, fluticasone propionate.
Description
25 mcg/125 mcg MDI: Each actuation delivers: Salmeterol (as xinafoate) 25 mcg, Fluticasone Propionate 125 mcg.
25 mcg/250 mcg MDI: Each actuation delivers: Salmeterol (as xinafoate) 25 mcg, Fluticasone Propionate 250 mcg.
50 mcg/250 mcg DPI: Each dry powder for inhalation capsule contains: Salmeterol (as xinafoate) 50 mcg, Fluticasone propionate 250 mcg.
50 mcg/500 mcg DPI: Each dry powder for inhalation capsule contains: Salmeterol (as xinafoate) 50 mcg, Fluticasone propionate 500 mcg.
MDI: Salmeterol xinafoate is a selective long-acting (12 hours) β2-adrenoreceptor agonist with a long side chain which binds to the exo-site of the receptor. These pharmacological properties of salmeterol offer more effective protection against histamine-induced bronchoconstriction and produce a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting β2-agonists.
Fluticasone propionate given by inhalation at recommended doses has a potent 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. Daily output of adrenocortical hormones usually remain within the normal range during chronic treatment with inhaled fluticasone propionate, even at the highest recommended doses in children and adult. 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 stimulation test. However any residual impairment of adrenal reserve from the previous treatment may persist for a considerable time and should be borne in mind.
Action
Pharmacology: The combination represent 2 classes of medications (a synthetic corticosteroid and a selective, long-acting beta-adrenergic receptor agonist) that have different effects on clinical and physiological indices.
Fluticasone propionate: It is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. In vitro assays using human lung cytosol preparations have established fluticasone propionate as a human glucocorticosteroid receptor agonist with an affinity 18 times greater than dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate and over 3 times that of budesonide. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages and neutrophils) and mediator production or secretion (e.g. histamine, eicosanoids, leukotrienes and cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma. Inflammation is also a component in the pathogenesis of chronic obstructive pulmonary disease (COPD).
Salmeterol Xinafoate: It is a long-acting beta2-adrenergic agonist. The pharmacologic effect of Salmeterol Xinafoate is part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels caused relaxation of bronchial smooth muscle and inhibition of release mediators of immediate hypersensitivity from cells, especially from mast cells. In vitro tests shows that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediator, such as histamine, leukotrienes and prostaglandin D2, from human lung. Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet-activating factor-induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route.
Mechanism of Action: Salmeterol and Fluticasone propionate have different mode of action. Salmeterol protects against symptoms. Fluticasone propionate improves lung function and prevent exacerbations. Salmeterol + Fluticasone propionate can offer a more convenient regimen for patients on concurrent β-agonist and inhaled corticosteroid therapy.
Pharmacokinetics: 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. Even though plasma levels of Salmeterol + Fluticasone are very low. Potential interactions with other substrates and inhibitors of CYP 3A4 cannot be excluded. Salmeterol acts locally in the lungs 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 in the drug due to the low plasma concentrations at the therapeutic doses (approximately 200 mg/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 100 mg/mL, these concentrations are up to 1000 fold lower than the steady state levels observed in toxicity studies. In toxicity studies no detrimental effects have been seen following long term regular dosing (more than 12 months) in patients with airways obstruction.
Indications/Uses
MDI: Is indicated for the treatment in the regular treatment of reversible obstructive airways disease (ROAD), including asthma in children and adults, where use of a combination (bronchodilator and inhaled corticosteroid) is appropriate. This may include: Patients on effective maintenance doses of long acting β-agonist and inhaled corticosteroids; Patients who are asymptomatic on current inhaled corticosteroid therapy; Patients on regular bronchodilator therapy who require inhaled corticosteroid.
Also for the maintenance treatment of chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema.
DPI: For the maintenance and treatment of mild, moderate and severe persistent asthma in patient more than 5 years of age and in patients with chronic obstructive pulmonary disease.
Dosage/Direction for Use
MDI: Patient should be regularly reassessed by a physician so that the strength of Salmeterol + Fluticasone propionate they are receiving remains optimal and is only changed on medical advice.
Reversible Obstructive airways Disease (ROAD): The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. Salmeterol + Fluticasone propionate should be given the strength containing the appropriate dosage for the severity of the disease.
Recommended Doses: For Adults and Adolescents 12 years and older: Two (2) inhalations of 25 mcg salmeterol and 50 mcg fluticasone propionate two (2) times a day.
Two (2) inhalations of 25 mcg Salmeterol and 125 mcg Fluticasone propionate two (2) times a day.
Two (2) inhalations of 25 mcg Salmeterol and 250 mcg Fluticasone propionate two (2) times a day.
Children 4 years and older: Two (2) inhalations of 25 mcg Salmeterol and 50 mcg Fluticasone propionate two (2) times a day.
There are no data available for use of Salmeterol and 50 mcg Fluticasone propionate in children aged less than 4 years old.
Chronic Obstructive Pulmonary Disease (COPD): For adult patients the maximum recommended dose is two (2) inhalations 25/250 mcg Salmeterol + Fluticasone propionate twice daily.
DPI: Adults and adolescents 12 years and over: 1 capsule a day, or as prescribed by the physician.
Chronic Obstructive Pulmonary Disease (COPD): 1 capsule a day, or as prescribed by the physician.
Contraindications
Hypersensitivity to salmeterol and corticosteroid or its components, previous history of paradoxical bronchospasm.
Special Precautions
MDI: Increasing use of short acting bronchodilators to relieve symptoms indicates deteriorations of control and patients should be reviewed by the physicians. Sudden and progressive deterioration in control of asthma is potentially life-threatening and patient should be reviewed by the physician. Consideration should be given to increasing corticosteroid therapy. Also, where the current dosage of salmeterol + Fluticasone propionate has failed to give adequate control of ROAD, the patient should be reviewed by physician. For patients with COPD, considerations should be given to additional corticosteroid therapies and administration of antibiotics if an exacerbation is associated with infection. Treatment with salmeterol + fluticasone propionate should not be stopped abruptly in patients with asthma due to risk exacerbation; therapy should be titrated-down under physician supervision. For patients with COPD, cessation of therapy may be associated with symptomatic decomposition and should be supervised by physician.
Should be administered with caution in patients with active or quiescent pulmonary tuberculosis, thyrotoxicosis, systemic effects may occur with inhaled corticosteroid, particularly at high doses prescribed for long periods; these effects are much likely to occur than with oral corticosteroids. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored.
DPI: Avoid using salmeterol as sole agent for asthma control. Patients should be instructed to stop salmeterol when they have breakthrough asthma symptoms or acute asthma exacerbation and to shift to short acting selective B2-agonist. Avoid use during pregnancy.
Adverse Reactions
MDI: Adverse events which have been associated with salmeterol or fluticasone propionate are given as follows.
Includes tachycardia, palpitations, cardiac arrhythmias, precipitation of angina pectoris, CNS stimulations, dry mouth, sweating, headache, dizziness, nausea, vomiting, nervousness, anxiety and tremor.
The side-effects associated with the use of corticosteroids in the large doses often necessary to produce a therapeutic response results from excessive action on electrolyte balance, excessive action on other aspects of metabolism including gluconeogenesis, the action on tissue repair & healing, and an inhibitory effects on the secretion of corticotrophin by the anterior lobe of the pituitary gland.
Hypersensitivity reactions have occurred with corticosteroids, mainly when administered topically.
DPI: Salmeterol may cause fine tremor of skeletal muscle (particularly the hands), palpitations, tachycardia, nervous tensions, headaches, peripheral vasodilatation, and rarely muscle cramps. Inhalation causes fewer side-effects than systemic administration, and the more selective beta2-agonist cause fewer side-effect than less selective beta agonists. Potentially serious hypokalemia has been reported after large doses. Hypersensitivity reactions have occurred, including paradoxical bronchospasm, angioedema, urticaria, hypotension, and collapse.
Fluticasone hypersensitivity reactions may occur. Eosinophilic conditions, including Churg-Strauss syndrome, have been reported rarely, in most cases following a transfer from oral corticosteroid therapy. Inhalation administration of large amounts of fluticasone propionate may produce systemic effects also. The adverse effects of corticosteroid may result from unwanted mineralocorticoid or glucocorticoid actions, or from inhibition of the hypothalamic-pituitary-adrenal axis. Despite the fact that inhaled fluticasone is generally thought to lack systemic effects at therapeutic doses, a study in 25 healthy subjects indicated that fluticasone propionate as single inhaled doses of 250, 500 and 1000 μg did produce a reduction in plasma cortisol, indicating suppression with fluticasone, particularly at high doses, and the effect may be more marked with repeated than with single doses.
Drug Interactions
MDI: Both non-selective and selective β-blockers should be avoided unless there are compelling reasons for the use. Due to the very low plasma concentrations achieved after inhaled dosing clinically significant drug interactions are unlikely. Care should be taken when co-administering known strong CYP3A's inhibitors (e.g. Ketoconazole, Ritonavir) as there is potential for increased systemic exposure to Fluticasone propionate.
Administration of drugs during pregnancy and lactation should be considered if the expected benefit to the mother is greater than any possible risk to the fetus or child.
DPI: Salmeterol and other beta2 agonist with corticosteroids, diuretics, or xanthines increases the risk of hypokalaemia, and monitoring of potassium concentrations is recommended in severe asthma, where such combination therapy is the rule. For an outline of interactions associated with sympathomimetics in general.
Fluticasone concurrent use of barbiturates, carbamazepine, phenytoin, primidone, or rifampicin may enhance the metabolism and reduce the effects of systemic corticosteroids. Conversely, oral contraceptives or ritonavir may increase plasma concentrations of corticosteroids. Use of corticosteroids with potassium depleting diuretics, such as thiazides or frusemide may cause excessive potassium loss.
Caution For Usage
MDI: Instructions for Use/Handling: Before using for the first time or if the inhaler has not been used for a week or more remove the metal canister and mouth piece cover out of the inhaler rinse the plastic body and mouth piece cover under running tap water and shake it well to remove excess water and leave it dry in warm place. After drying re-assemble and lace back in the outer plastic container.
Using the Inhaler: 1. Take off the cap and shake the inhaler.
2. Breathe out all the way.
3. Hold the inhaler 1 to 2 inches in front of the mouth (about the width of 2 fingers).
4. Start breathing in slowly through the mouth, and then press down on the inhaler one time. Breathe in slowly, as deeply as the patient can.
5. Slowly count to 10 while holding the breath (if the patient can). This lets the medicine reach deep into the lungs.
6. If the doctor prescribed more than 1 puff of medicine, repeat procedure, starting with step 2.
7. Rinse the mouth afterwards, to remove residue of the medicine.
Usage by children: Parents must assist children who need help in the proper use of inhaler.
DPI: Direction for Use: Remove the cap of the INNOhaler.
Steadily hold the base and open the INNOhaler turning the nozzle counterclockwise (see the arrow on the nozzle itself).
Introduce the capsule into the loading chamber.
Close the nozzle turning it counterclockwise.
Thoroughly press the two buttons, keeping the INNOhaler in vertical position.
Deeply breathe out.
Introduce the whole nozzle into the mouth and breathe in, closing the lips (avoid air passing around the nozzle). Try it again (three to four times), till the capsule is completely empty.
After use, extract the empty capsule and close the INNOhaler.
Storage
MDI: Store at temperatures not exceeding 25°C.
DPI: Store at temperatures not exceeding 30°C.
ATC Classification
R03AK06 - salmeterol and fluticasone ; Belongs to the class of adrenergics in combination with corticosteroids or other drugs, excluding anticholinergics. Used in the treatment of obstructive airway diseases.
Presentation/Packing
25 mcg/125 mcg MDI 1's. 25 mcg/250 mcg MDI 1's. 50 mcg/250 mcg DPI (w/ Innohaler) 40's. 50 mcg/500 mcg DPI (w/ Innohaler) 40's.
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