ADEFLO MDI 250 Salmeterol Xinafoate / Fluticasone Propionate 50mcg / 250mcg / act. Metered-Dose Inhaler 120act.
RXDRUG-DRP-6878-01
Discreet Packaging
FDA-registered Products
FDA-licensed Pharmacies
Indications/Uses
Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler is indicated in the regular treatment of asthma where use of a combination product (long-acting beta-2-agonist and inhaled corticosteroid) is appropriate: Patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled short acting beta-2 agonist.
Or, patients already adequately controlled on both inhaled corticosteroid and long-acting beta-2-agonist.
Or, patients already adequately controlled on both inhaled corticosteroid and long-acting beta-2-agonist.
Dosage/Direction for Use
Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler is for inhalation use only.
Patients should be made aware that Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler must be used daily for optimum benefit, even when asymptomatic.
Patients should be regularly reassessed by a doctor, so that the strength of Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler they are receiving remains optimal and is only changed on medical advice. 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 the lowest strength of the combination given twice daily then the next step could include a test of inhaled corticosteroid alone. As an alternative, patients requiring a long acting beta-2-agonist could be titrated to Salmeterol and Fluticasone Propionate Pressurized Inhalation.
CFC Free inhaler given once daily if, in the opinion of the prescriber, it would be adequate to maintain disease control. In the event of once daily dosing when the patient has a history of nocturnal symptoms the dose should be given at night and when the patient has a history of mainly day-time symptoms the dose should be given in the morning.
Patients should be given the strength of Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler containing the appropriate Fluticasone propionate dosage for the severity of their disease.
Note: Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 25 + 50 micrograms strength is not appropriate in adults and children with severe asthma. Prescribers should be aware that, in patients with asthma, Fluticasone propionate is as effective as other inhaled steroids at approximately half the microgram daily dose. If an individual patient should require dosages outside the recommended regimen, appropriate doses of beta-agonist and/or corticosteroid should be prescribed.
Recommended Doses: Adults and adolescents 12 years and older: Two inhalations of 25 micrograms Salmeterol and 50 micrograms Fluticasone propionate twice daily.
Or, two inhalations of 25 micrograms Salmeterol and 125 micrograms Fluticasone propionate twice daily.
Or, two inhalations of 25 micrograms Salmeterol and 250 micrograms Fluticasone propionate twice daily.
A short term trial of Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 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 two inhalations of 25 micrograms Salmeterol and 50 micrograms Fluticasone propionate twice daily. Once control of asthma is attained treatment should be reviewed and consideration given as to whether patients should be stopped down to an Inhaled corticosteroid alone. Regular review of patients as treatment Is stopped 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. Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler is not intended for the initial management of mild asthma. Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 25 micrograms/50 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 and older: Two inhalations of 25 micrograms Salmeterol and 50 micrograms Fluticasone propionate twice daily.
The maximum licensed dose of Fluticasone propionate delivered by Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler in children is 100 microgram twice daily. There are no data available for use of Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free Inhaler in children aged under 4 years.
Patients should be instructed in the proper use and care of their inhaler and their technique checked to ensure optimum delivery of the inhaled drug to the lungs.
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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler in patients with hepatic Impairment.
Instructions for Use: Patients should be instructed in the proper use of their inhaler.
During inhalation, the patient should preferably sit or stand. The inhaler has been designed for use in an inverted position.
Patients should be made aware that Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler must be used daily for optimum benefit, even when asymptomatic.
Patients should be regularly reassessed by a doctor, so that the strength of Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler they are receiving remains optimal and is only changed on medical advice. 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 the lowest strength of the combination given twice daily then the next step could include a test of inhaled corticosteroid alone. As an alternative, patients requiring a long acting beta-2-agonist could be titrated to Salmeterol and Fluticasone Propionate Pressurized Inhalation.
CFC Free inhaler given once daily if, in the opinion of the prescriber, it would be adequate to maintain disease control. In the event of once daily dosing when the patient has a history of nocturnal symptoms the dose should be given at night and when the patient has a history of mainly day-time symptoms the dose should be given in the morning.
Patients should be given the strength of Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler containing the appropriate Fluticasone propionate dosage for the severity of their disease.
Note: Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 25 + 50 micrograms strength is not appropriate in adults and children with severe asthma. Prescribers should be aware that, in patients with asthma, Fluticasone propionate is as effective as other inhaled steroids at approximately half the microgram daily dose. If an individual patient should require dosages outside the recommended regimen, appropriate doses of beta-agonist and/or corticosteroid should be prescribed.
Recommended Doses: Adults and adolescents 12 years and older: Two inhalations of 25 micrograms Salmeterol and 50 micrograms Fluticasone propionate twice daily.
Or, two inhalations of 25 micrograms Salmeterol and 125 micrograms Fluticasone propionate twice daily.
Or, two inhalations of 25 micrograms Salmeterol and 250 micrograms Fluticasone propionate twice daily.
A short term trial of Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 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 two inhalations of 25 micrograms Salmeterol and 50 micrograms Fluticasone propionate twice daily. Once control of asthma is attained treatment should be reviewed and consideration given as to whether patients should be stopped down to an Inhaled corticosteroid alone. Regular review of patients as treatment Is stopped 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. Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler is not intended for the initial management of mild asthma. Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 25 micrograms/50 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 and older: Two inhalations of 25 micrograms Salmeterol and 50 micrograms Fluticasone propionate twice daily.
The maximum licensed dose of Fluticasone propionate delivered by Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler in children is 100 microgram twice daily. There are no data available for use of Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free Inhaler in children aged under 4 years.
Patients should be instructed in the proper use and care of their inhaler and their technique checked to ensure optimum delivery of the inhaled drug to the lungs.
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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler in patients with hepatic Impairment.
Instructions for Use: Patients should be instructed in the proper use of their inhaler.
During inhalation, the patient should preferably sit or stand. The inhaler has been designed for use in an inverted position.
Overdosage
There are no data available from clinical trials on overdose with Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler; however data on overdose with both drugs are given as follows: The signs and symptoms of Salmeterol overdose are tremor, headache and tachycardia. The preferred antidotes are cardioselective beta-blocking agents, which should be used with caution in patients with a history of bronchospasm. If Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler therapy has to be withdrawn due to overdose of the beta agonist component of the drug, provision of appropriate replacement steroid therapy should be considered. Additionally, hypokalemia can occur and potassium replacement should be considered.
Acute: Acute Inhalation of Fluticasone propionate doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not need emergency action as adrenal function is recovered in a low days, as verified by plasma cortisol measurements.
Chronic overdose of inhaled Fluticasone propionate: Refer to Precautions: risk of adrenal suppression.
Monitoring of adrenal reserve may be necessary. In cases of Fluticasone propionate overdose Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler therapy may still be continued at a suitable dosage for symptom control.
Acute: Acute Inhalation of Fluticasone propionate doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not need emergency action as adrenal function is recovered in a low days, as verified by plasma cortisol measurements.
Chronic overdose of inhaled Fluticasone propionate: Refer to Precautions: risk of adrenal suppression.
Monitoring of adrenal reserve may be necessary. In cases of Fluticasone propionate overdose Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler therapy may still be continued at a suitable dosage for symptom control.
Contraindications
Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler is contraindicated in patients with hypersensitivity to any of the active substances or to the excipients.
Special Precautions
The management of asthma should normally follow a stepwise programme and patient response should be monitored clinically and by lung function tests.
Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler.
Increasing use of short-acting bronchodilators to relieve asthma symptoms indicates deterioration of asthma 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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler has failed to give adequate control of asthma. Consideration should be given to additional corticosteroid therapies.
Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler. Regular review of patients as treatment is stopped down is important. The lowest effective dose of Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler should be used.
Treatment with Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler should not be stopped abruptly.
As with all inhaled medication containing corticosteroids, Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler should be administered with caution in patients with pulmonary tuberculosis.
Rarely, Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 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. Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
Care should be taken when transferring patients to Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free Inhaler 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. Those 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 behavioural effects including psychomotor hyperactivity, sloop 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 loss 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.
Systemic absorption of salmeterol and fluticasone propionate Is largely through the lungs. As the use of a spacer device with a metered dose inhaler may increase drug delivery to the lungs it should be noted that this could potentially lead to an increase in the risk of systemic adverse effects.
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 resolve 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.
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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free Inhaler 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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler.
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 OTc 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.
Interaction with other medicinal products and other forms of interaction: Both non-selective and selective beta-blockers should be avoided in patients with asthma, 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 arc 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 CYP3A4 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.
Use in Children: Children and adolescents <16 years 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.
Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler.
Increasing use of short-acting bronchodilators to relieve asthma symptoms indicates deterioration of asthma 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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler has failed to give adequate control of asthma. Consideration should be given to additional corticosteroid therapies.
Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler. Regular review of patients as treatment is stopped down is important. The lowest effective dose of Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler should be used.
Treatment with Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler should not be stopped abruptly.
As with all inhaled medication containing corticosteroids, Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler should be administered with caution in patients with pulmonary tuberculosis.
Rarely, Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 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. Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
Care should be taken when transferring patients to Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free Inhaler 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. Those 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 behavioural effects including psychomotor hyperactivity, sloop 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 loss 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.
Systemic absorption of salmeterol and fluticasone propionate Is largely through the lungs. As the use of a spacer device with a metered dose inhaler may increase drug delivery to the lungs it should be noted that this could potentially lead to an increase in the risk of systemic adverse effects.
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 resolve 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.
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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free Inhaler 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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler.
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 OTc 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.
Interaction with other medicinal products and other forms of interaction: Both non-selective and selective beta-blockers should be avoided in patients with asthma, 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 arc 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 CYP3A4 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.
Use in Children: Children and adolescents <16 years 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.
Use In Pregnancy & Lactation
Use in 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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 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.
Use in 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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Administration of Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 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.
Use in 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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Adverse Reactions
As Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler 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 as follows, 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) and not known (cannot be estimated from the available data). Frequencies were derived from clinical trial data. The incidence in placebo was not taken into account. (See table.)
Adverse events which have been associated with Salmeterol/Fluticasone propionate are given as follows, 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) and not known (cannot be estimated from the available data). Frequencies were derived from clinical trial data. The incidence in placebo was not taken into account. (See table.)
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 Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler.
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.
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.
Drug Interactions
Both non-selective and selective beta-blockers should be avoided in patients with asthma, 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 OTc 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 (500 mg orally three times a day) and Salmeterol (50 micrograms inhaled twice daily) in 15 healthy subjects for 6 days resulted in a small but non-statistically significant increase in Salmeterol exposure (1.4-fold Cmax and 1.2-fold AUC). Co-administration with erythromycin was not associated with any serious adverse effects.
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 OTc 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 (500 mg orally three times a day) and Salmeterol (50 micrograms inhaled twice daily) in 15 healthy subjects for 6 days resulted in a small but non-statistically significant increase in Salmeterol exposure (1.4-fold Cmax and 1.2-fold AUC). Co-administration with erythromycin was not associated with any serious adverse effects.
Caution For Usage
Instructions for patient for using the inhaler without spacer: Important: Follow instructions carefully.
Shake the inhaler well immediately before each use.
Testing the inhaler: If the patient is using the inhaler for the first time or if the inhaler has not been used for a minimum of seven days, "test spray" the inhaler. Remove the cap from the mouthpiece; the mouthpiece should be inspected for the presence of foreign objects before each use. Spray the inhaler 2 times into the air after shaking the device prior to each actuation.
Make sure the canister is fully and firmly inserted into the actuator.
Hold the inhaler upright with the thumb on the base. Place either one or two fingers on the top of the canister. Breathe out fully through the mouth expelling as much air from the lungs as possible. Thereafter, place the mouthpiece of the inhaler in the mouth between the teeth.
Close the lips around it (do not bite) tilt the head slightly backwards. Start breathing in slowly through the mouth. As the patient breathes in steadily and deeply, press down the canister to release on puff.
While holding the breath, patients should take off the inhaler from the mouth and should continue holding their breath for 10 seconds or for as long as it is comfortable. Breath out slowly.
Note: If the second dose is required wait for at least one minute and repeat steps 2 through 5 for each puff prescribed by the physician. Rinse mouth or gargle with water after inhaling recommended dose (Single dose means total number of puffs advised by the physician at once). This is likely to reduce the soreness that may be caused by the drug. After use, replace the mouthpiece cover.
Practice in front of the mirror for the first few times. If the patient see "mist" coming from top of the inhaler or sides of the mouth, this indicates failure of technique.
For Children: Children should use the inhaler under adult supervision, as instructed by the Physician.
Cleaning: Clean the inhaler at least once in a week.
Gently pull the metal canister out of the plastic body of the inhaler. Remove the mouthpiece cover.
Rinse the plastic body and the mouthpiece cover in warm/running water.
Dry thoroughly. Avoid excess heat.
Replace the canister and the mouthpiece cover correctly.
Discard the inhaler along with the canister after using the labeled number of inhalation. DO NOT PUT THE METAL CONTAINER IN WATER.
Warnings: The metal canister is pressurized. Do not use or store near heat or open flame. Exposure to temperature above 120°F (48.9°C) may cause bursting. Never throw container into fire or incinerator even when apparently empty. Avoid spraying in eyes.
Shake the inhaler well immediately before each use.
Testing the inhaler: If the patient is using the inhaler for the first time or if the inhaler has not been used for a minimum of seven days, "test spray" the inhaler. Remove the cap from the mouthpiece; the mouthpiece should be inspected for the presence of foreign objects before each use. Spray the inhaler 2 times into the air after shaking the device prior to each actuation.
Make sure the canister is fully and firmly inserted into the actuator.
Hold the inhaler upright with the thumb on the base. Place either one or two fingers on the top of the canister. Breathe out fully through the mouth expelling as much air from the lungs as possible. Thereafter, place the mouthpiece of the inhaler in the mouth between the teeth.
Close the lips around it (do not bite) tilt the head slightly backwards. Start breathing in slowly through the mouth. As the patient breathes in steadily and deeply, press down the canister to release on puff.
While holding the breath, patients should take off the inhaler from the mouth and should continue holding their breath for 10 seconds or for as long as it is comfortable. Breath out slowly.
Note: If the second dose is required wait for at least one minute and repeat steps 2 through 5 for each puff prescribed by the physician. Rinse mouth or gargle with water after inhaling recommended dose (Single dose means total number of puffs advised by the physician at once). This is likely to reduce the soreness that may be caused by the drug. After use, replace the mouthpiece cover.
Practice in front of the mirror for the first few times. If the patient see "mist" coming from top of the inhaler or sides of the mouth, this indicates failure of technique.
For Children: Children should use the inhaler under adult supervision, as instructed by the Physician.
Cleaning: Clean the inhaler at least once in a week.
Gently pull the metal canister out of the plastic body of the inhaler. Remove the mouthpiece cover.
Rinse the plastic body and the mouthpiece cover in warm/running water.
Dry thoroughly. Avoid excess heat.
Replace the canister and the mouthpiece cover correctly.
Discard the inhaler along with the canister after using the labeled number of inhalation. DO NOT PUT THE METAL CONTAINER IN WATER.
Warnings: The metal canister is pressurized. Do not use or store near heat or open flame. Exposure to temperature above 120°F (48.9°C) may cause bursting. Never throw container into fire or incinerator even when apparently empty. Avoid spraying in eyes.
Storage
Store at temperatures not exceeding 30°C. Do not freeze.
Action
Pharmacotherapeutic group: Adrenergics and other anti-asthmatics.
Pharmacology: Pharmacodynamics: Mechanism of action: Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler contains Salmeterol and Fluticasone propionate which have differing modes of action.
The respective mechanisms of action of both drugs are discussed as follows.
Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenocoptor 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, with less adverse effects than when corticosteroids are administered systemically.
Clinical Study: In a randomized, open label, non-inferiority, comparative, multicentric study of 12-weeks of treatment period HFA-propelled salmeterol/fluticasone (25/250 micrograms) pressurized Metered Dose Inhaler (Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler) was compared with HFA-propelled Seretide (25/250 micrograms) pMDI (pressurized Metered Dose Inhaler) in patients with persistent asthma. Out of total 372 subjects, 186 subjects (mean age of 42.68 years) were randomized to HFA-propelled salmeterol/fluticasone (25/250 micrograms) pMDI group and 186 subjects (mean ago of 44.67 years) were randomized to HFA-propelled Seretide (25/250 micrograms) pMDI group. All subjects were Asian with 56.18% male and 43.82% female.
The results of the study showed that for the primary efficacy endpoint Forced expiratory volume in one second (FEV1) absolute value was comparable between the HFA-propelled salmeterol/fluticasone (25/250 micrograms) pMDI and HFA-propelled Seretide (25/250 micrograms) pMDI.
The lower limit of the 95% confidence interval for the difference in FEV1 between groups was greater than the non-inferiority margin of -15% (on negative scale) of adjusted mean FEV1 of HFA-propelled Seretide (25/250 micrograms) pMDI in per protocol (PP) and Intent to treat (ITT) population.
Overall 46/372 (12.3%) patients experienced at least one adverse event during the study. Patient with at least one adverse event were 13.4% in the HFA-Propelled Salmeterol/Fluticasone (25/250 micrograms) pMDI group and 11.3% in the HFA-Propelled Seretide (25/250 micrograms) pMDI group.
The most frequent treatment emergent adverse events were reported in the respiratory, thoracic and mediastinal disorders and occurred in 7% of patients in the HFA-Propelled Salmeterol/Fluticasone (25/250 micrograms) pMDI group and 3.2% of patients in the HFA-Propelled Seretide (25/250 micrograms) pMDI group.
Most of the adverse events were mild in severity and resolved without treatment. Adverse events considered moderate were observed for 4 patients in the HFA-Propelled Salmeterol/Fluticasone (25/250 micrograms) pMDI group and 3 patients in the HFA-Propelled Seretide (25/250 micrograms) pMDI group. There were no severe AEs reported in the study.
There were no withdrawals due to adverse events or unexpected safety findings reported during the study. There were no unexpected AEs as per Prescribing Information of HFA-Propelled Seretide (25/250 micrograms) pMDI. There were no clinically significant change observed from baseline to end of treatment in clinical laboratory evaluations, vital signs, ECG and physical examinations.
Two patients in the HFA-Propelled Salmeterol/Fluticasone (25/250 micrograms) pMDI group experienced AEs which were related to study drug. No patients in the HFA-Propelled Seretide (25/250 micrograms) pMDI group experienced AEs which were related to study drug.
Fourty-Eight (48) patients (24 patients in each arm) also participated in the pharmacokinetic and 24 hour urine cortisol part of the study. Salmeterol plasma concentrations with respect to Cmax and AUC0-tau were observed to be higher in test product as compared to reference product at week4; however there was no significant difference between the two treatment groups for systemic β2-mediated adverse effects. For fluticasone plasma concentrations. Cmax and AUC0-tau values were observed to be lower in the test product as compared to reference product and 24-h urinary cortisol excretion was reported to be higher in test product versus reference, hence there was no hypothalamic pituitary-adrenal (HPA) axis suppression.
The study concluded that HFA-Propelled Salmeterol/Fluticasone (25/250 micrograms) pMDI was safe, well tolerated and non-inferior in efficacy compared to HFA.
Pharmacokinetics: When Salmeterol and Fluticasone propionate were administered in combination by the inhaled route, the pharmacokinetics of each component were similar to those observed when the drugs were administered separately. For pharmacokinetic purposes therefore each component can be considered separately.
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 duo to the low plasma concentrations at therapeutic doses (approximately 200 picogram/mL or less) achieved after inhaled dosing.
Fluticasone propionate: 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. In patients with asthma a lesser degree of systemic exposure to inhaled Fluticasone propionate has been observed.
Systemic absorption occurs mainly through the lungs and is initially rapid then 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 characterised 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 91%.
Fluticasone propionate is cleared very rapidly from the systemic circulation. The main pathway is metabolize to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Other unidentified metabolites are also found in the faeces.
The renal clearance of Fluticasone propionate is negligible. Less than 5% of the dose is excreted in urine, mainly as metabolites. The main part of the dose is excreted as faeces as metabolites and unchanged drug.
Toxicology: Preclinical safety data: The only safety concerns for human use derived from animal studies of salmeterol and fluticasone propionate given separately were effects associated with exaggerated pharmacological actions.
In animal reproduction studies, glucocorticosteroids have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant for man given recommended doses. Animal studies with salmeterol have shown embryofoetal toxicity only at high exposure levels. Following co-administration, increased incidences of transposed umbilical artery and incomplete ossification of occipital bone were found in rats at doses associated with known glucocorticoid-induced abnormalities.
The non-CFC propellant, Norflurane (HFA134a), has been shown to have no toxic effect at very high vapour concentrations, far in excess of those likely to be experienced by patients, in a wide range of animal species exposed daily for periods of two years.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Fluticasone Propionate: Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 5 times the MRHD on a mcg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (less than the MRHD on a mcg/m2 basis) for 104 weeks.
Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse micronucleus test. No evidence of impairment of fertility was observed in reproductive studies conducted in rats at subcutaneous doses up to 50 mcg/kg (less than the MRHD on a mcg/m2 basis). Prostate weight was significantly reduced.
Salmeterol: In an 18-month carcinogenicity study in CD-mice, Salmeterol at oral doses of 1.4 mg/kg and above (approximately two times the MRHD based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. No tumors wore seen at 0.2 mg/kg (approximately 2 times the MRHD for adults based on comparison of the AUCs). In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, Salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 80 times the MRHD on a mg/m2 basis). No tumors were soon at 0.21 mg/kg (approximately 25 times the MRHD on a mg/m2 basis) These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in rats treated with Salmeterol at oral doses up to 2 mg/kg (approximately 230 times the MRHD on a mg/m2 basis).
Pharmacology: Pharmacodynamics: Mechanism of action: Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler contains Salmeterol and Fluticasone propionate which have differing modes of action.
The respective mechanisms of action of both drugs are discussed as follows.
Salmeterol: Salmeterol is a selective long-acting (12 hour) beta-2-adrenocoptor 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, with less adverse effects than when corticosteroids are administered systemically.
Clinical Study: In a randomized, open label, non-inferiority, comparative, multicentric study of 12-weeks of treatment period HFA-propelled salmeterol/fluticasone (25/250 micrograms) pressurized Metered Dose Inhaler (Salmeterol and Fluticasone Propionate Pressurized Inhalation CFC Free inhaler) was compared with HFA-propelled Seretide (25/250 micrograms) pMDI (pressurized Metered Dose Inhaler) in patients with persistent asthma. Out of total 372 subjects, 186 subjects (mean age of 42.68 years) were randomized to HFA-propelled salmeterol/fluticasone (25/250 micrograms) pMDI group and 186 subjects (mean ago of 44.67 years) were randomized to HFA-propelled Seretide (25/250 micrograms) pMDI group. All subjects were Asian with 56.18% male and 43.82% female.
The results of the study showed that for the primary efficacy endpoint Forced expiratory volume in one second (FEV1) absolute value was comparable between the HFA-propelled salmeterol/fluticasone (25/250 micrograms) pMDI and HFA-propelled Seretide (25/250 micrograms) pMDI.
The lower limit of the 95% confidence interval for the difference in FEV1 between groups was greater than the non-inferiority margin of -15% (on negative scale) of adjusted mean FEV1 of HFA-propelled Seretide (25/250 micrograms) pMDI in per protocol (PP) and Intent to treat (ITT) population.
Overall 46/372 (12.3%) patients experienced at least one adverse event during the study. Patient with at least one adverse event were 13.4% in the HFA-Propelled Salmeterol/Fluticasone (25/250 micrograms) pMDI group and 11.3% in the HFA-Propelled Seretide (25/250 micrograms) pMDI group.
The most frequent treatment emergent adverse events were reported in the respiratory, thoracic and mediastinal disorders and occurred in 7% of patients in the HFA-Propelled Salmeterol/Fluticasone (25/250 micrograms) pMDI group and 3.2% of patients in the HFA-Propelled Seretide (25/250 micrograms) pMDI group.
Most of the adverse events were mild in severity and resolved without treatment. Adverse events considered moderate were observed for 4 patients in the HFA-Propelled Salmeterol/Fluticasone (25/250 micrograms) pMDI group and 3 patients in the HFA-Propelled Seretide (25/250 micrograms) pMDI group. There were no severe AEs reported in the study.
There were no withdrawals due to adverse events or unexpected safety findings reported during the study. There were no unexpected AEs as per Prescribing Information of HFA-Propelled Seretide (25/250 micrograms) pMDI. There were no clinically significant change observed from baseline to end of treatment in clinical laboratory evaluations, vital signs, ECG and physical examinations.
Two patients in the HFA-Propelled Salmeterol/Fluticasone (25/250 micrograms) pMDI group experienced AEs which were related to study drug. No patients in the HFA-Propelled Seretide (25/250 micrograms) pMDI group experienced AEs which were related to study drug.
Fourty-Eight (48) patients (24 patients in each arm) also participated in the pharmacokinetic and 24 hour urine cortisol part of the study. Salmeterol plasma concentrations with respect to Cmax and AUC0-tau were observed to be higher in test product as compared to reference product at week4; however there was no significant difference between the two treatment groups for systemic β2-mediated adverse effects. For fluticasone plasma concentrations. Cmax and AUC0-tau values were observed to be lower in the test product as compared to reference product and 24-h urinary cortisol excretion was reported to be higher in test product versus reference, hence there was no hypothalamic pituitary-adrenal (HPA) axis suppression.
The study concluded that HFA-Propelled Salmeterol/Fluticasone (25/250 micrograms) pMDI was safe, well tolerated and non-inferior in efficacy compared to HFA.
Pharmacokinetics: When Salmeterol and Fluticasone propionate were administered in combination by the inhaled route, the pharmacokinetics of each component were similar to those observed when the drugs were administered separately. For pharmacokinetic purposes therefore each component can be considered separately.
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 duo to the low plasma concentrations at therapeutic doses (approximately 200 picogram/mL or less) achieved after inhaled dosing.
Fluticasone propionate: 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. In patients with asthma a lesser degree of systemic exposure to inhaled Fluticasone propionate has been observed.
Systemic absorption occurs mainly through the lungs and is initially rapid then 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 characterised 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 91%.
Fluticasone propionate is cleared very rapidly from the systemic circulation. The main pathway is metabolize to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Other unidentified metabolites are also found in the faeces.
The renal clearance of Fluticasone propionate is negligible. Less than 5% of the dose is excreted in urine, mainly as metabolites. The main part of the dose is excreted as faeces as metabolites and unchanged drug.
Toxicology: Preclinical safety data: The only safety concerns for human use derived from animal studies of salmeterol and fluticasone propionate given separately were effects associated with exaggerated pharmacological actions.
In animal reproduction studies, glucocorticosteroids have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant for man given recommended doses. Animal studies with salmeterol have shown embryofoetal toxicity only at high exposure levels. Following co-administration, increased incidences of transposed umbilical artery and incomplete ossification of occipital bone were found in rats at doses associated with known glucocorticoid-induced abnormalities.
The non-CFC propellant, Norflurane (HFA134a), has been shown to have no toxic effect at very high vapour concentrations, far in excess of those likely to be experienced by patients, in a wide range of animal species exposed daily for periods of two years.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Fluticasone Propionate: Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 5 times the MRHD on a mcg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (less than the MRHD on a mcg/m2 basis) for 104 weeks.
Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse micronucleus test. No evidence of impairment of fertility was observed in reproductive studies conducted in rats at subcutaneous doses up to 50 mcg/kg (less than the MRHD on a mcg/m2 basis). Prostate weight was significantly reduced.
Salmeterol: In an 18-month carcinogenicity study in CD-mice, Salmeterol at oral doses of 1.4 mg/kg and above (approximately two times the MRHD based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. No tumors wore seen at 0.2 mg/kg (approximately 2 times the MRHD for adults based on comparison of the AUCs). In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, Salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 80 times the MRHD on a mg/m2 basis). No tumors were soon at 0.21 mg/kg (approximately 25 times the MRHD on a mg/m2 basis) These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in rats treated with Salmeterol at oral doses up to 2 mg/kg (approximately 230 times the MRHD on a mg/m2 basis).
MedsGo Class
Antiasthmatic & COPD Preparations
Features
Brand
Adeflo Mdi 250
Full Details
Dosage Strength
25 mcg / 250 mcg per Actuation
Drug Ingredients
- Fluticasone
- Salmeterol
Drug Packaging
Metered-Dose Inhaler 120act.
Generic Name
Salmeterol Xinafoate / Fluticasone Propionate
Dosage Form
Metered-Dose Inhaler
Registration Number
DRP-6878-01
Drug Classification
Prescription Drug (RX)
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