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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).
