FORAIR 250 Salmeterol Xinafoate / Fluticasone Propionate 25mcg / 250mcg per actuation Metered-Dose Inhaler 120actuations 1's
RXDRUG-DR-XY39639
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Features
Brand
FORAIR 250
Full Details
Dosage Strength
25mcg / 250mcg / act.
Drug Ingredients
- Fluticasone
- Salmeterol
Drug Packaging
Metered-Dose Inhaler 1's
Generic Name
Salmeterol Xinafoate / Fluticasone Propionate
Dosage Form
Metered-Dose Inhaler
Registration Number
DR-XY39639
Drug Classification
Prescription Drug (RX)
Description
Indications/Uses
Forair is indicated in the regular treatment of asthma, where use of a combination product (bronchodilator and inhaled corticosteroid) has been found to be beneficial.
The efficacy of the combination of Salmeterol and Fluticasone in the dry powder form in the management of patients with COPD has been reported in recent clinical studies.
Reversible airways obstruction (including nocturnal asthma and prevention of exercise induced bronchospasm) in patients requiring long term regular bronchodilator. Chronic Obstructive pulmonary disease.
The efficacy of the combination of Salmeterol and Fluticasone in the dry powder form in the management of patients with COPD has been reported in recent clinical studies.
Reversible airways obstruction (including nocturnal asthma and prevention of exercise induced bronchospasm) in patients requiring long term regular bronchodilator. Chronic Obstructive pulmonary disease.
Dosage/Direction for Use
Adults and adolescents 12 years and over: Forair 50: 2 inhalations twice daily.
Forair 125: 2 inhalations twice daily.
Forair 250: 2 inhalations twice daily
Children 4 years and elder: Forair 50: 2 inhalations twice daily.
In young patients or in patients who have difficulty using an MDI, an Aerolife spacer device may be used with Forair inhaler.
Special groups: No dose adjustment is warranted in the elderly or in those with renal impairment.
Using the Forair Inhaler: Patients to be carefully instructed in proper use of the inhaler.
Forair 125: 2 inhalations twice daily.
Forair 250: 2 inhalations twice daily
Children 4 years and elder: Forair 50: 2 inhalations twice daily.
In young patients or in patients who have difficulty using an MDI, an Aerolife spacer device may be used with Forair inhaler.
Special groups: No dose adjustment is warranted in the elderly or in those with renal impairment.
Using the Forair Inhaler: Patients to be carefully instructed in proper use of the inhaler.
Overdosage
There are no data available from clinical trials on overdose with Forair, 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 cardio selective beta-blocking agents, which should be used with caution in patients with a history of bronchospasm. If Forair 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, hypokalaemia 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 few days, as verified by plasma cortical measurements.
Chronic overdose of inhaled Fluticasone propionate: Risk of adrenal suppression. Monitoring of adrenal reserve may be necessary. In cases of Fluticasone propionate overdose Forair 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 few days, as verified by plasma cortical measurements.
Chronic overdose of inhaled Fluticasone propionate: Risk of adrenal suppression. Monitoring of adrenal reserve may be necessary. In cases of Fluticasone propionate overdose Forair therapy may still be continued at a suitable dosage for symptom control.
Contraindications
The combination of Fluticasone and Salmeterol is not indicated for use in the treatment of acute bronchospasm. It is contraindicated for use in the primary treatment of status asthmaticus or other acute episodes where intensive measures are required.
Special Precautions
The management of asthma should normally follow a stepwise programme and patient response should be monitored clinically and by lung function tests.
Forair 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. Forair is not intended for the initial management of asthma until the need for and approximate dosage of corticosteroids has been established.
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 Forair has failed to give adequate control of asthma. Consideration should be given to additional corticosteroid therapies.
Treatment with Forair should not be stopped abruptly.
As with all inhaled medication containing corticosteroids, Forair should be administered with caution in patients with pulmonary tuberculosis.
Forair should be administered with caution in patients with severe cardiovascular disorders, including heart rhythm abnormalities, diabetes mellitus, untreated hypokalaemia or thyrotoxicosis.
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.
Potentially serious hypokalaemia may result from systemic beta-2-agonist therapy, but following inhalation at therapeutic doses plasma levels of Salmeterol are very low.
As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. Forair should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
Care should be taken when transferring patients to Forair therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy.
Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained.
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored.
Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children and adolescents <16 years taking high doses of Fluticasone (typically ≥1000 mcg/day) may be at particular risk. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of Fluticasone propionate between 500 and less than 1000 mcg. 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.
As systemic absorption is largely through the lungs, the use of a spacer plus 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 minimize 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.
Use in Pregnancy: Fertility: Fluticasone: No evidence of impairment of fertility was seen in studies done on male and female rats at subcutaneous doses up to 50 mcg/kg (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg.
Salmeterol: No effects on fertility were found in male and female rats treated with Salmeterol at oral doses up to 2 mg/kg (approximately 180 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis).
Fluticasone and Salmeterol combination: No evidence of enhanced toxicity was seen in studies done using the combination of Fluticasone and Salmeterol as compared to the use of the drugs individually. In mice, the combination of 150 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) with 10 mg/kg orally of Salmeterol (approximately 450 times the maximum recommended daily inhalation dose in adults on a mg per m2 basis) was teratogenic. Cleft palate, fetal death, increased implantation loss and delayed ossification were seen. These observations are characteristic of glucocorticoids. No developmental toxicity was observed at combination doses up to 40 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) and up to 1.4 mg/kg orally of Salmeterol (approximately 65 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis).
In rats, there was no teratogenicity observed at combination doses up to 30 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) and up to 1 mg/kg of Salmeterol (approximately 90 times the MRD inhalation dose in adults on a mcg/m2 basis). Combining 100 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg/m2 basis) with 10 mg/kg orally of Salmeterol (approximately 900 times the MRD inhalation dose in adults on a mcg/m2 basis) produced maternal toxicity, decreased placental weight, decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone.
There are no adequate and well controlled studies of the combination of Fluticasone and Salmeterol in pregnant women. It should be used during pregnancy only when the potential benefit justifies the potential risk to the fetus.
Pregnancy Category C: Fluticasone: Studies in mice and rats at subcutaneous doses of Fluticasone at 45 and 100 mcg/kg, respectively (less than or equivalent to the MRD inhalation dose in adults on a mcg/m2 basis) found fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. Studies in rabbits at subcutaneous doses of 4 mcg/kg (less than the MRD inhalation dose in adults on a mcg/m2 basis) found fetal weight reduction and cleft palate. However, no teratogenic effects were reported at oral doses of up to 300 mcg/kg (approximately 5 times the MRD inhalation dose in adults on a mcg/m2 basis); in addition, no Fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration.
Fluticasone propionate crosses the placenta following a subcutaneous dose of 100 mcg /kg to mice (less than the MRD inhalation dose in adults on a mcg/m2 basis); subcutaneous or oral administration of 100 mcg/kg to rats (approximately equivalent to the MRD in adults on a mcg/m2 basis) or 300 mcg/kg to rabbits (approximately 5 times the MRD inhalation dose in adults on a mcg/m2 basis).
Experience suggests that rodents are more susceptible to the teratogenic effects of pharmacologic doses of oral glucocorticoids than are humans. Additionally, because production of glucocorticoids increases naturally during pregnancy, most women will require a lower
exogenous glucocorticoids dose and many may not need glucocorticoids treatment during pregnancy.
Pregnancy Category C: Salmeterol: Rats given oral doses of 2 mg/kg of Salmeterol (approximately 180 times the maximum recommended daily inhalation dose (MRD) in adults on a mg/m2 basis) experienced no teratogenic effects. In pregnant Dutch rabbits given oral doses of 1 mg per kg and above (approximately 50 times the MRD based on the comparison of the AUCs) toxic effects were shown in the fetus. The developed effects were considered to be characteristic of beta-adrenergic stimulation (i.e., precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones). No significant effects occurred at 20 times the recommended human clinical dose based on AUC comparisons. New Zealand white rabbits were less sensitive, and the exposure to oral doses of 10 mg/kg (approximately 1800 times the recommended human clinical dose based on mg/m2 basis) produced only delayed ossification of frontal bones.
Salmeterol crossed the placenta following oral administration of 10 mg/kg to mice and rats (approximately 450 and 900 times, respectively, the recommended human clinical dose based on mg/m2 basis).
Use in Lactation: Labor and delivery: There are no well controlled human studies that have investigated the effects of the combination of Fluticasone and Salmeterol on pre-term labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, the use of the drug for management of asthma during labor should be restricted to those patients in whom the benefit clearly outweighs the risk.
Breast-feeding: It is not known whether the combination of Fluticasone and Salmeterol is distributed into breast milk. Caution should be used when administering to nursing women.
Fluticasone: It is not known whether Fluticasone is distributed into breast milk, however other corticosteroids have been detected in human milk. After subcutaneous administration of triturated Fluticasone at a 10 mcg per kg dose (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) to lactating rats resulted in measurable radioactivity in milk.
Salmeterol: It is not known whether Salmeterol is distributed into breast milk, however Salmeterol Xinafoate is distributed in rat's milk.
Use in Children: Official product labeling states that the safety and efficacy of Fluticasone and Salmeterol have not been established in children under 12 years of age in the U.S., or in children under 4 years of age in Canada. Recent controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect was observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, which suggests that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than are some commonly used tests of HPA axis function.
The long-term effects of this reduction in growth velocity, including the impact on the final adult height, are unknown. The potential for "catch up" growth following the discontinuation of treatment has not been adequately studied. The growth of pediatric patients receiving orally inhaled corticosteroids should be monitored routinely. If the patient appears to have growth suppression, the possibility that they are particularly sensitive to the effects of corticosteroids should be considered. The potential effects on growth velocity of prolonged treatment with inhaled corticosteroids should be weighed against the clinical benefits obtained and the availability of safe and effective noncorticosteroid treatment alternatives. To minimize the systemic effects of orally inhaled corticosteroids, the dose should be titrated to the lowest effective dose for the patient.
Use in Elderly: Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of Fluticasone and Salmeterol in the elderly. However, elderly patients are more likely to have age related medical problems such as cardiovascular disease which may require adjustment of dosing and using caution in patients receiving Fluticasone and Salmeterol.
Forair 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. Forair is not intended for the initial management of asthma until the need for and approximate dosage of corticosteroids has been established.
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 Forair has failed to give adequate control of asthma. Consideration should be given to additional corticosteroid therapies.
Treatment with Forair should not be stopped abruptly.
As with all inhaled medication containing corticosteroids, Forair should be administered with caution in patients with pulmonary tuberculosis.
Forair should be administered with caution in patients with severe cardiovascular disorders, including heart rhythm abnormalities, diabetes mellitus, untreated hypokalaemia or thyrotoxicosis.
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.
Potentially serious hypokalaemia may result from systemic beta-2-agonist therapy, but following inhalation at therapeutic doses plasma levels of Salmeterol are very low.
As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. Forair should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
Care should be taken when transferring patients to Forair therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy.
Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained.
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored.
Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children and adolescents <16 years taking high doses of Fluticasone (typically ≥1000 mcg/day) may be at particular risk. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of Fluticasone propionate between 500 and less than 1000 mcg. 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.
As systemic absorption is largely through the lungs, the use of a spacer plus 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 minimize 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.
Use in Pregnancy: Fertility: Fluticasone: No evidence of impairment of fertility was seen in studies done on male and female rats at subcutaneous doses up to 50 mcg/kg (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg.
Salmeterol: No effects on fertility were found in male and female rats treated with Salmeterol at oral doses up to 2 mg/kg (approximately 180 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis).
Fluticasone and Salmeterol combination: No evidence of enhanced toxicity was seen in studies done using the combination of Fluticasone and Salmeterol as compared to the use of the drugs individually. In mice, the combination of 150 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) with 10 mg/kg orally of Salmeterol (approximately 450 times the maximum recommended daily inhalation dose in adults on a mg per m2 basis) was teratogenic. Cleft palate, fetal death, increased implantation loss and delayed ossification were seen. These observations are characteristic of glucocorticoids. No developmental toxicity was observed at combination doses up to 40 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) and up to 1.4 mg/kg orally of Salmeterol (approximately 65 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis).
In rats, there was no teratogenicity observed at combination doses up to 30 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) and up to 1 mg/kg of Salmeterol (approximately 90 times the MRD inhalation dose in adults on a mcg/m2 basis). Combining 100 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg/m2 basis) with 10 mg/kg orally of Salmeterol (approximately 900 times the MRD inhalation dose in adults on a mcg/m2 basis) produced maternal toxicity, decreased placental weight, decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone.
There are no adequate and well controlled studies of the combination of Fluticasone and Salmeterol in pregnant women. It should be used during pregnancy only when the potential benefit justifies the potential risk to the fetus.
Pregnancy Category C: Fluticasone: Studies in mice and rats at subcutaneous doses of Fluticasone at 45 and 100 mcg/kg, respectively (less than or equivalent to the MRD inhalation dose in adults on a mcg/m2 basis) found fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. Studies in rabbits at subcutaneous doses of 4 mcg/kg (less than the MRD inhalation dose in adults on a mcg/m2 basis) found fetal weight reduction and cleft palate. However, no teratogenic effects were reported at oral doses of up to 300 mcg/kg (approximately 5 times the MRD inhalation dose in adults on a mcg/m2 basis); in addition, no Fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration.
Fluticasone propionate crosses the placenta following a subcutaneous dose of 100 mcg /kg to mice (less than the MRD inhalation dose in adults on a mcg/m2 basis); subcutaneous or oral administration of 100 mcg/kg to rats (approximately equivalent to the MRD in adults on a mcg/m2 basis) or 300 mcg/kg to rabbits (approximately 5 times the MRD inhalation dose in adults on a mcg/m2 basis).
Experience suggests that rodents are more susceptible to the teratogenic effects of pharmacologic doses of oral glucocorticoids than are humans. Additionally, because production of glucocorticoids increases naturally during pregnancy, most women will require a lower
exogenous glucocorticoids dose and many may not need glucocorticoids treatment during pregnancy.
Pregnancy Category C: Salmeterol: Rats given oral doses of 2 mg/kg of Salmeterol (approximately 180 times the maximum recommended daily inhalation dose (MRD) in adults on a mg/m2 basis) experienced no teratogenic effects. In pregnant Dutch rabbits given oral doses of 1 mg per kg and above (approximately 50 times the MRD based on the comparison of the AUCs) toxic effects were shown in the fetus. The developed effects were considered to be characteristic of beta-adrenergic stimulation (i.e., precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones). No significant effects occurred at 20 times the recommended human clinical dose based on AUC comparisons. New Zealand white rabbits were less sensitive, and the exposure to oral doses of 10 mg/kg (approximately 1800 times the recommended human clinical dose based on mg/m2 basis) produced only delayed ossification of frontal bones.
Salmeterol crossed the placenta following oral administration of 10 mg/kg to mice and rats (approximately 450 and 900 times, respectively, the recommended human clinical dose based on mg/m2 basis).
Use in Lactation: Labor and delivery: There are no well controlled human studies that have investigated the effects of the combination of Fluticasone and Salmeterol on pre-term labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, the use of the drug for management of asthma during labor should be restricted to those patients in whom the benefit clearly outweighs the risk.
Breast-feeding: It is not known whether the combination of Fluticasone and Salmeterol is distributed into breast milk. Caution should be used when administering to nursing women.
Fluticasone: It is not known whether Fluticasone is distributed into breast milk, however other corticosteroids have been detected in human milk. After subcutaneous administration of triturated Fluticasone at a 10 mcg per kg dose (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) to lactating rats resulted in measurable radioactivity in milk.
Salmeterol: It is not known whether Salmeterol is distributed into breast milk, however Salmeterol Xinafoate is distributed in rat's milk.
Use in Children: Official product labeling states that the safety and efficacy of Fluticasone and Salmeterol have not been established in children under 12 years of age in the U.S., or in children under 4 years of age in Canada. Recent controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect was observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, which suggests that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than are some commonly used tests of HPA axis function.
The long-term effects of this reduction in growth velocity, including the impact on the final adult height, are unknown. The potential for "catch up" growth following the discontinuation of treatment has not been adequately studied. The growth of pediatric patients receiving orally inhaled corticosteroids should be monitored routinely. If the patient appears to have growth suppression, the possibility that they are particularly sensitive to the effects of corticosteroids should be considered. The potential effects on growth velocity of prolonged treatment with inhaled corticosteroids should be weighed against the clinical benefits obtained and the availability of safe and effective noncorticosteroid treatment alternatives. To minimize the systemic effects of orally inhaled corticosteroids, the dose should be titrated to the lowest effective dose for the patient.
Use in Elderly: Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of Fluticasone and Salmeterol in the elderly. However, elderly patients are more likely to have age related medical problems such as cardiovascular disease which may require adjustment of dosing and using caution in patients receiving Fluticasone and Salmeterol.
Use In Pregnancy & Lactation
Use in Pregnancy: Fertility: Fluticasone: No evidence of impairment of fertility was seen in studies done on male and female rats at subcutaneous doses up to 50 mcg/kg (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg.
Salmeterol: No effects on fertility were found in male and female rats treated with Salmeterol at oral doses up to 2 mg/kg (approximately 180 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis).
Fluticasone and Salmeterol combination: No evidence of enhanced toxicity was seen in studies done using the combination of Fluticasone and Salmeterol as compared to the use of the drugs individually. In mice, the combination of 150 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) with 10 mg/kg orally of Salmeterol (approximately 450 times the maximum recommended daily inhalation dose in adults on a mg per m2 basis) was teratogenic. Cleft palate, fetal death, increased implantation loss and delayed ossification were seen. These observations are characteristic of glucocorticoids. No developmental toxicity was observed at combination doses up to 40 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) and up to 1.4 mg/kg orally of Salmeterol (approximately 65 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis).
In rats, there was no teratogenicity observed at combination doses up to 30 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) and up to 1 mg/kg of Salmeterol (approximately 90 times the MRD inhalation dose in adults on a mcg/m2 basis). Combining 100 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg/m2 basis) with 10 mg/kg orally of Salmeterol (approximately 900 times the MRD inhalation dose in adults on a mcg/m2 basis) produced maternal toxicity, decreased placental weight, decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone.
There are no adequate and well controlled studies of the combination of Fluticasone and Salmeterol in pregnant women. It should be used during pregnancy only when the potential benefit justifies the potential risk to the fetus.
Pregnancy Category C: Fluticasone: Studies in mice and rats at subcutaneous doses of Fluticasone at 45 and 100 mcg/kg, respectively (less than or equivalent to the MRD inhalation dose in adults on a mcg/m2 basis) found fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. Studies in rabbits at subcutaneous doses of 4 mcg/kg (less than the MRD inhalation dose in adults on a mcg/m2 basis) found fetal weight reduction and cleft palate. However, no teratogenic effects were reported at oral doses of up to 300 mcg/kg (approximately 5 times the MRD inhalation dose in adults on a mcg/m2 basis); in addition, no Fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration.
Fluticasone propionate crosses the placenta following a subcutaneous dose of 100 mcg /kg to mice (less than the MRD inhalation dose in adults on a mcg/m2 basis); subcutaneous or oral administration of 100 mcg/kg to rats (approximately equivalent to the MRD in adults on a mcg/m2 basis) or 300 mcg/kg to rabbits (approximately 5 times the MRD inhalation dose in adults on a mcg/m2 basis).
Experience suggests that rodents are more susceptible to the teratogenic effects of pharmacologic doses of oral glucocorticoids than are humans. Additionally, because production of glucocorticoids increases naturally during pregnancy, most women will require a lower
exogenous glucocorticoids dose and many may not need glucocorticoids treatment during pregnancy.
Pregnancy Category C: Salmeterol: Rats given oral doses of 2 mg/kg of Salmeterol (approximately 180 times the maximum recommended daily inhalation dose (MRD) in adults on a mg/m2 basis) experienced no teratogenic effects. In pregnant Dutch rabbits given oral doses of 1 mg per kg and above (approximately 50 times the MRD based on the comparison of the AUCs) toxic effects were shown in the fetus. The developed effects were considered to be characteristic of beta-adrenergic stimulation (i.e., precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones). No significant effects occurred at 20 times the recommended human clinical dose based on AUC comparisons. New Zealand white rabbits were less sensitive, and the exposure to oral doses of 10 mg/kg (approximately 1800 times the recommended human clinical dose based on mg/m2 basis) produced only delayed ossification of frontal bones.
Salmeterol crossed the placenta following oral administration of 10 mg/kg to mice and rats (approximately 450 and 900 times, respectively, the recommended human clinical dose based on mg/m2 basis).
Use in Lactation: Labor and delivery: There are no well controlled human studies that have investigated the effects of the combination of Fluticasone and Salmeterol on pre-term labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, the use of the drug for management of asthma during labor should be restricted to those patients in whom the benefit clearly outweighs the risk.
Breast-feeding: It is not known whether the combination of Fluticasone and Salmeterol is distributed into breast milk. Caution should be used when administering to nursing women.
Fluticasone: It is not known whether Fluticasone is distributed into breast milk, however other corticosteroids have been detected in human milk. After subcutaneous administration of triturated Fluticasone at a 10 mcg per kg dose (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) to lactating rats resulted in measurable radioactivity in milk.
Salmeterol: It is not known whether Salmeterol is distributed into breast milk, however Salmeterol Xinafoate is distributed in rat's milk.
Salmeterol: No effects on fertility were found in male and female rats treated with Salmeterol at oral doses up to 2 mg/kg (approximately 180 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis).
Fluticasone and Salmeterol combination: No evidence of enhanced toxicity was seen in studies done using the combination of Fluticasone and Salmeterol as compared to the use of the drugs individually. In mice, the combination of 150 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) with 10 mg/kg orally of Salmeterol (approximately 450 times the maximum recommended daily inhalation dose in adults on a mg per m2 basis) was teratogenic. Cleft palate, fetal death, increased implantation loss and delayed ossification were seen. These observations are characteristic of glucocorticoids. No developmental toxicity was observed at combination doses up to 40 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) and up to 1.4 mg/kg orally of Salmeterol (approximately 65 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis).
In rats, there was no teratogenicity observed at combination doses up to 30 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) and up to 1 mg/kg of Salmeterol (approximately 90 times the MRD inhalation dose in adults on a mcg/m2 basis). Combining 100 mcg/kg subcutaneously of Fluticasone (less than the maximum recommended daily inhalation dose in adults on a mg/m2 basis) with 10 mg/kg orally of Salmeterol (approximately 900 times the MRD inhalation dose in adults on a mcg/m2 basis) produced maternal toxicity, decreased placental weight, decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone.
There are no adequate and well controlled studies of the combination of Fluticasone and Salmeterol in pregnant women. It should be used during pregnancy only when the potential benefit justifies the potential risk to the fetus.
Pregnancy Category C: Fluticasone: Studies in mice and rats at subcutaneous doses of Fluticasone at 45 and 100 mcg/kg, respectively (less than or equivalent to the MRD inhalation dose in adults on a mcg/m2 basis) found fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. Studies in rabbits at subcutaneous doses of 4 mcg/kg (less than the MRD inhalation dose in adults on a mcg/m2 basis) found fetal weight reduction and cleft palate. However, no teratogenic effects were reported at oral doses of up to 300 mcg/kg (approximately 5 times the MRD inhalation dose in adults on a mcg/m2 basis); in addition, no Fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration.
Fluticasone propionate crosses the placenta following a subcutaneous dose of 100 mcg /kg to mice (less than the MRD inhalation dose in adults on a mcg/m2 basis); subcutaneous or oral administration of 100 mcg/kg to rats (approximately equivalent to the MRD in adults on a mcg/m2 basis) or 300 mcg/kg to rabbits (approximately 5 times the MRD inhalation dose in adults on a mcg/m2 basis).
Experience suggests that rodents are more susceptible to the teratogenic effects of pharmacologic doses of oral glucocorticoids than are humans. Additionally, because production of glucocorticoids increases naturally during pregnancy, most women will require a lower
exogenous glucocorticoids dose and many may not need glucocorticoids treatment during pregnancy.
Pregnancy Category C: Salmeterol: Rats given oral doses of 2 mg/kg of Salmeterol (approximately 180 times the maximum recommended daily inhalation dose (MRD) in adults on a mg/m2 basis) experienced no teratogenic effects. In pregnant Dutch rabbits given oral doses of 1 mg per kg and above (approximately 50 times the MRD based on the comparison of the AUCs) toxic effects were shown in the fetus. The developed effects were considered to be characteristic of beta-adrenergic stimulation (i.e., precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones). No significant effects occurred at 20 times the recommended human clinical dose based on AUC comparisons. New Zealand white rabbits were less sensitive, and the exposure to oral doses of 10 mg/kg (approximately 1800 times the recommended human clinical dose based on mg/m2 basis) produced only delayed ossification of frontal bones.
Salmeterol crossed the placenta following oral administration of 10 mg/kg to mice and rats (approximately 450 and 900 times, respectively, the recommended human clinical dose based on mg/m2 basis).
Use in Lactation: Labor and delivery: There are no well controlled human studies that have investigated the effects of the combination of Fluticasone and Salmeterol on pre-term labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, the use of the drug for management of asthma during labor should be restricted to those patients in whom the benefit clearly outweighs the risk.
Breast-feeding: It is not known whether the combination of Fluticasone and Salmeterol is distributed into breast milk. Caution should be used when administering to nursing women.
Fluticasone: It is not known whether Fluticasone is distributed into breast milk, however other corticosteroids have been detected in human milk. After subcutaneous administration of triturated Fluticasone at a 10 mcg per kg dose (less than the maximum recommended daily inhalation dose in adults on a mg per m2 basis) to lactating rats resulted in measurable radioactivity in milk.
Salmeterol: It is not known whether Salmeterol is distributed into breast milk, however Salmeterol Xinafoate is distributed in rat's milk.
Adverse Reactions
Nausea, dizziness, arthralgia, rash, very rare dyspepsia, hyperglycemia. Hoarseness of voice/dysphonia, throat irritation, headache, fungal (candidial) infections of the mouth and throat. To minimize the occurrence of fungal infections it is advisable for the patients to rinse the mouth after each dose.
As with any combination containing corticosteroids, particularly if prescribed at high doses and for prolonged periods, systemic effects like adrenal suppression, decrease in bone mineral density are possible. Due to the targeted delivery of Forair Inhaler to the airways, the chances of these systemic side effects are minimal.
As with any combination containing corticosteroids, particularly if prescribed at high doses and for prolonged periods, systemic effects like adrenal suppression, decrease in bone mineral density are possible. Due to the targeted delivery of Forair Inhaler to the airways, the chances of these systemic side effects are minimal.
Drug Interactions
Concurrent administration with the following should be avoided: Antidepressants, tricyclic or Monoamine oxidase (MAO); Beta-adrenergic receptor blocking agents; Diuretics, potassium-depleting or Diuretics, thiazide; Ketoconazole or Cytochrome P450 inhibitors.
Storage
Store at temperatures not exceeding 25°C. Do not freeze.
Keep away from eyes.
Shake well before each use.
Keep away from eyes.
Shake well before each use.
Action
Pharmacology: Mechanism of Action: Fluticasone acts as a human glucocorticoid receptor agonist with an affinity for the receptor that is 18 times greater than that of dexamethasone, almost twice that of beclomethasone-17-monopropionate, and over three times that of budesonide. The anti-inflammatory actions of Fluticasone may contribute to its efficacy in asthma; however, its precise mechanisms are unknown. Corticosteroids have been shown to inhibit mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils. Corticosteroids also inhibit production or secretion of cell mediators such as histamine, leukotrienes, cytokines, and eicosanoids.
Salmeterol is a long acting beta-adrenergic agonist. It acts by stimulating beta2-adrenergic receptors in the lungs to relax bronchial smooth muscle, thereby relieving bronchospasm. This action is believed to result from increased production of cyclic adenosine 3,5-monophosphate (cyclic 3,5-AMP; cAMP) and ensuing reduction in intracellular calcium concentration caused by activation of the enzyme adenylate cyclase that catalyzes the conversion of adenosine triphosphate (ATP) to cAMP. Increased cAMP concentrations, in addition to relaxing bronchial smooth muscle, inhibit release of mediators of immediate hypersensitivity from cells, especially from mast cells.
Pharmacodynamics: Both Salmeterol and Fluticasone propionate have high lipocity and long duration of effect at their sites of action in the lung. The bronchodilator effect of Salmeterol lasts for about 12 hours as a result of high affinity binding to receptors within the β2-adrenoreceptor like wise Fluticasone has affinity for the glucocorticoid receptor and the half-life of the steroid receptor complex is >10 hrs.
Salmeterol and Fluticasone target different aspects of the disease process and varied evidence suggests that they produce complex mechanisms to produce relief of airway function.
Salmeterol protects against histamine, methacholine, cold air and sulphur dioxide-induced constriction and exercise induced asthma. There is no evidence of tolerance to the bronchodilator effects of Salmeterol. Salmeterol may also have anti-inflammatory properties
and can attenuate hyper responsiveness in patients with asthma.
Fluticasone propionate inhibits eosinophil activity resulting from the subsequent release of inflammatory mediators. It also appears to reduce bronchial hyper responsiveness in patients with asthma.
Given in fixed combination, the systemic dynamic effects of both Salmeterol and Fluticasone are essentially unchanged compared with their effects when given independently. No evidence of any untoward interactions between Salmeterol and Fluticasone was observed.
Pharmacokinetics: Pharmacokinetics of the fixed combination has not yet been established.
When Salmeterol is inhaled, plasma concentration of the drug cannot be detected even at 30 minutes after administration of the therapeutic doses. Nevertheless, in studies of single and multiple dose Salmeterol, there was no evidence that concomitant administration of Fluticasone propionate caused any alteration in the systemic availability of the drug versus monotherapy.
Similarly the systemic availability of Fluticasone propionate following inhalation is low, and studies comparing Fluticasone propionate monotherapy with each formulation strength of fixed combination Salmeterol and Fluticasone propionate indicated no increase in the systemic availability of the latter when Salmeterol was given concomitantly.
Both Salmeterol and Fluticasone propionate are metabolized by the cytochrome P450 enzyme CYP3A4, extensively so in the case of Fluticasone propionate, but only partly so in the case of Salmeterol.
Absorption: Fluticasone Oral bioavailability is less than 1%, due to incomplete absorption and presystemic metabolism in the intestine and liver. Systemic bioavailability via the DISKUS device averages 18%.
Salmeterol Systemic levels are low or undetectable after inhalation, due to small doses.
Distribution: Volume of distribution (VolD): Fluticasone: 4.2 L per kg (L/kg).
Protein binding: Fluticasone Very high (91%).
Salmeterol Very high (96%).
Biotransformation: Fluticasone: Total clearance is high; average 1093 mL per minute. The primary metabolite is the 17 β-carboxylic acid derivative of Fluticasone (via cytochrome P450 3A4).
Salmeterol: Metabolized by hydroxylation.
Half-life: Elimination: Fluticasone: 7.8 hours.
Salmeterol: 5.5 hours.
Time to peak concentration: Fluticasone: 1 to 2 hours following administration.
Salmeterol: 5 minutes following administration.
Peak plasma concentration: Fluticasone: Ranged from undetectable to 266 pg per mL after a 500 mcg twice daily dose. Mean concentration: 110 pg per mL.
Salmeterol: Mean concentrations: 167 pg per mL over 20 minutes following a chronic dosing schedule.
Elimination: Fluticasone: Renal: Less than 5%.
Fecal: Remainder of dose.
Salmeterol: Renal: 25%.
Fecal: 60%.
Salmeterol is a long acting beta-adrenergic agonist. It acts by stimulating beta2-adrenergic receptors in the lungs to relax bronchial smooth muscle, thereby relieving bronchospasm. This action is believed to result from increased production of cyclic adenosine 3,5-monophosphate (cyclic 3,5-AMP; cAMP) and ensuing reduction in intracellular calcium concentration caused by activation of the enzyme adenylate cyclase that catalyzes the conversion of adenosine triphosphate (ATP) to cAMP. Increased cAMP concentrations, in addition to relaxing bronchial smooth muscle, inhibit release of mediators of immediate hypersensitivity from cells, especially from mast cells.
Pharmacodynamics: Both Salmeterol and Fluticasone propionate have high lipocity and long duration of effect at their sites of action in the lung. The bronchodilator effect of Salmeterol lasts for about 12 hours as a result of high affinity binding to receptors within the β2-adrenoreceptor like wise Fluticasone has affinity for the glucocorticoid receptor and the half-life of the steroid receptor complex is >10 hrs.
Salmeterol and Fluticasone target different aspects of the disease process and varied evidence suggests that they produce complex mechanisms to produce relief of airway function.
Salmeterol protects against histamine, methacholine, cold air and sulphur dioxide-induced constriction and exercise induced asthma. There is no evidence of tolerance to the bronchodilator effects of Salmeterol. Salmeterol may also have anti-inflammatory properties
and can attenuate hyper responsiveness in patients with asthma.
Fluticasone propionate inhibits eosinophil activity resulting from the subsequent release of inflammatory mediators. It also appears to reduce bronchial hyper responsiveness in patients with asthma.
Given in fixed combination, the systemic dynamic effects of both Salmeterol and Fluticasone are essentially unchanged compared with their effects when given independently. No evidence of any untoward interactions between Salmeterol and Fluticasone was observed.
Pharmacokinetics: Pharmacokinetics of the fixed combination has not yet been established.
When Salmeterol is inhaled, plasma concentration of the drug cannot be detected even at 30 minutes after administration of the therapeutic doses. Nevertheless, in studies of single and multiple dose Salmeterol, there was no evidence that concomitant administration of Fluticasone propionate caused any alteration in the systemic availability of the drug versus monotherapy.
Similarly the systemic availability of Fluticasone propionate following inhalation is low, and studies comparing Fluticasone propionate monotherapy with each formulation strength of fixed combination Salmeterol and Fluticasone propionate indicated no increase in the systemic availability of the latter when Salmeterol was given concomitantly.
Both Salmeterol and Fluticasone propionate are metabolized by the cytochrome P450 enzyme CYP3A4, extensively so in the case of Fluticasone propionate, but only partly so in the case of Salmeterol.
Absorption: Fluticasone Oral bioavailability is less than 1%, due to incomplete absorption and presystemic metabolism in the intestine and liver. Systemic bioavailability via the DISKUS device averages 18%.
Salmeterol Systemic levels are low or undetectable after inhalation, due to small doses.
Distribution: Volume of distribution (VolD): Fluticasone: 4.2 L per kg (L/kg).
Protein binding: Fluticasone Very high (91%).
Salmeterol Very high (96%).
Biotransformation: Fluticasone: Total clearance is high; average 1093 mL per minute. The primary metabolite is the 17 β-carboxylic acid derivative of Fluticasone (via cytochrome P450 3A4).
Salmeterol: Metabolized by hydroxylation.
Half-life: Elimination: Fluticasone: 7.8 hours.
Salmeterol: 5.5 hours.
Time to peak concentration: Fluticasone: 1 to 2 hours following administration.
Salmeterol: 5 minutes following administration.
Peak plasma concentration: Fluticasone: Ranged from undetectable to 266 pg per mL after a 500 mcg twice daily dose. Mean concentration: 110 pg per mL.
Salmeterol: Mean concentrations: 167 pg per mL over 20 minutes following a chronic dosing schedule.
Elimination: Fluticasone: Renal: Less than 5%.
Fecal: Remainder of dose.
Salmeterol: Renal: 25%.
Fecal: 60%.
MedsGo Class
Antiasthmatic & COPD Preparations
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