Salmeterol Fluticasone Inhalation Powder

1. Pharmacology and Toxicology (1) Mechanism of Action Seretide contains salmeterol and fluticasone propionate, which have different modes of action. Salmeterol acts to control symptoms, while fluticasone propionate improves lung function and prevents disease progression. Seretide can provide a more convenient regimen for patients who are taking β-agonists and inhaled corticosteroids at the same time. The respective mechanisms of action of the two drugs are described as follows: Salmeterol: The molecular structure of salmeterol is a long chain that can bind to the receptor's external site. It is a selective long-acting (12 hours) β2-adrenergic receptor agonist. Compared with the recommended dose of traditional short-acting β2-agonists, the pharmacological properties of salmeterol can provide more effective protection against histamine-induced bronchoconstriction and produce a more sustained bronchodilator effect that lasts at least 12 hours. In vitro experiments have shown that salmeterol can inhibit the release of mast cell mediators (such as histamine, leukotrienes and prostaglandin D2) in human lungs and is a potent and long-acting inhibitor. Salmeterol inhibits both immediate and delayed responses to inhaled allergens, with the latter effect lasting for more than 30 hours after a single inhalation dose until there is no longer a significant bronchodilator effect. A single dose of salmeterol can reduce bronchial hyperresponsiveness. These properties suggest that salmeterol also has non-bronchodilator activity, but its full clinical significance is unclear. This mechanism is different from the anti-inflammatory effect of corticosteroids. Fluticasone propionate: Inhaled fluticasone propionate at recommended doses produces a potent glucocorticoid anti-inflammatory effect in the lungs, thereby alleviating asthma symptoms and exacerbations without the side effects of systemic corticosteroids. During long-term inhaled fluticasone propionate therapy, daily adrenal corticosteroid secretion remains within the normal range, even at the maximum recommended dose for children and adults. When switching from other inhaled corticosteroids, daily adrenal corticosteroid secretion gradually improves despite past and current intermittent use of oral corticosteroids, indicating that adrenal function can be restored to normal during inhaled fluticasone propionate. During long-term treatment, adrenal reserve also remains normal, and normal proliferation can be detected by stimulation tests. However, it must be kept in mind that any impairment of adrenal reserve left over from previous treatment may persist for a considerable period of time. (2) Preclinical safety data The safety of salmeterol xinafoate and fluticasone propionate has been extensively evaluated by animal toxicity studies. Significant toxicity only occurred when the dose exceeded the recommended human dose, and all were expected responses to potent β2 adrenergic receptor agonists and glucocorticoids. In long-term studies, salmeterol xinafoate caused benign leiomyomata in the rat ovarian mesentery and mouse uterus. Rodents are sensitive to the formation of tumors induced by these drugs. Salmeterol is not considered to have a significant carcinogenic risk to humans. There is some cardiovascular interaction when salmeterol is used in combination with high-dose fluticasone propionate. In rats, it can temporarily cause mild atrial myocarditis and focal coronary arteritis, which can be relieved by conventional medication. When the combination is used, the increase in heart rate in dogs exceeds that when salmeterol is used alone. In human studies, no clinically relevant serious cardiovascular side effects have been found. In animals, co-administration did not change other types of related toxicity. 2. Pharmacokinetics There is no evidence in animals or humans that the simultaneous use of salmeterol and fluticasone propionate by inhalation will affect the pharmacokinetics of each component. Therefore, from a pharmacokinetic perspective, the two components can be considered separately. Although the plasma concentration of salmeterol is very low, the possibility of interaction with other substances and CYP3A4 inhibitors cannot be ruled out. (1) Salmeterol: Salmeterol acts locally in the lungs, so plasma levels are not used as a therapeutic indicator. In addition, data on the pharmacokinetics of salmeterol are limited. Because the plasma concentration of the drug after inhaled therapeutic doses is very low (about 200 pg/ml or less), it is technically difficult to detect the drug in plasma. After routine use of salmeterol, hydroxynaphthoic acid can be monitored in the systemic circulation, and its steady-state concentration reaches about 100 ng/ml. This concentration is more than 1000 times lower than the steady-state level observed in toxicity studies. No adverse effects have been observed in patients with airway obstruction who have been taking regular medication for a long time (more than 12 months). (2) Fluticasone propionate: Depending on the inhalation device, the absolute bioavailability of fluticasone propionate after inhalation is 10-30% of the normal dose. Systemic absorption occurs mainly in the lungs, which is rapid at first and then slows down. The remaining inhaled dose will be swallowed, but due to the low water solubility and pre-systemic metabolism of the drug, this method contributes very little to systemic absorption, and the final oral bioavailability is less than 1%. Systemic absorption increases linearly with the increase in inhaled dose. The distribution of fluticasone propionate is characterized by high plasma clearance (1150mL/min), large steady-state distribution volume (about 300L) and a terminal half-life of about 8 hours. It has a high plasma protein binding rate (91%). Fluticasone propionate is rapidly eliminated from the systemic circulation and is mainly metabolized by the cytochrome P450 enzyme CYP3A4 to an inactive carboxylic acid metabolite. Renal elimination of fluticasone propionate is negligible (<0.2%), and renal elimination of its metabolites is less than 5%. CYP3A4 inhibitors should be used with caution as these agents have the potential to increase systemic exposure of fluticasone propionate.

This product is a compound preparation, its components are: salmeterol (in the form of xinafoate) and fluticasone propionate. Each bubble contains 50 micrograms of salmeterol and 100 micrograms of fluticasone propionate; each bubble contains 50 micrograms of salmeterol and 250 micrograms of fluticasone propionate.

Seretide is indicated as a combination (bronchodilator and inhaled corticosteroid) for the conventional treatment of reversible obstructive airway disease, including asthma in adults and children. This may include: 1. Patients receiving effective maintenance doses of long-acting 2-agonists and inhaled corticosteroids. 2. Patients currently on inhaled corticosteroids but still have symptoms. 3. Patients receiving conventional treatment with bronchodilators but still require inhaled corticosteroids.

Seretide is for oral inhalation only. Patients should be made aware that the Seretide must be used regularly to achieve the desired benefit, even when symptoms are absent. Patients should be re-evaluated by their physician regularly to ensure that they are receiving the optimal dose of Seretide, and changes should be made only on the physician's advice. The dose should be adjusted to the minimum dose that maintains effective symptom control. Seretide containing an appropriate dose of fluticasone propionate should be prescribed to patients based on the severity of their condition. Recommended dose: Adults and adolescents 12 years and older: 1 inhalation (50 micrograms of salmeterol and 100 micrograms of fluticasone propionate) twice a day, or 1 inhalation (50 micrograms of salmeterol and 250 micrograms of fluticasone propionate) twice a day. Children 4 years and older: 1

Since Seretide contains salmeterol and fluticasone propionate, the type and severity of side effects associated with each component can be predicted. No other side effects were found when the two drugs were used together. The side effects related to salmeterol and fluticasone propionate are as follows: 1. Salmeterol has been reported to have pharmacological side effects of β2-agonists such as tremor, subjective palpitations and headache, but they are all temporary and alleviated with conventional treatment. Some patients may experience arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles). Usually sensitive patients. There have been reports of joint pain and allergic reactions including rash, edema and angioneurotic edema. There have been reports of oropharyngeal irritation. There have been rare reports of muscle spasms. 2. Some patients with fluticasone propionate may experience hoarseness and oropharyngeal beads.

It is contraindicated for those who have a history of allergy to any ingredient in this product.

Precautions for children: See [Dosage and Administration] and [Precautions]. Precautions for pregnancy and lactation: 1. There is no sufficient experience in the use of salmeterol and fluticasone propionate during human pregnancy and lactation. 2. In the reproductive toxicity study on animals, the expected effects on the fetus were found when the systemic exposure to excessive amounts of potent β2-adrenergic receptor agonists and glucocorticoids was used alone or in combination (see [Pharmacology and Toxicology]). 3. In the extensive clinical experience with these two types of drugs, no evidence was found that the above phenomenon was related to the therapeutic dose. Neither salmeterol xinafoate nor fluticasone propionate showed potential genotoxicity. 4. After inhalation of therapeutic doses, the plasma concentrations of salmeterol and fluticasone propionate are very low, so the concentrations in human milk are likely to be correspondingly low. This has been supported by studies on lactating animals, where the drug concentrations detected in milk are very low. Both salmeterol and fluticasone propionate can be excreted into rat milk. There is no information on human milk. 5. During pregnancy and lactation, the drug should only be considered when the expected benefit to the mother outweighs any possible harm to the fetus or child. For pregnant women, the dose of fluticasone propionate should be adjusted to the lowest effective dose that can adequately control asthma symptoms. 6. There is no data on human lactation. Both salmeterol and fluticasone propionate can be secreted into the milk of rats. This product can only be considered for use in lactating women when the expected benefit to the mother outweighs the possible risk to the child. Precautions for the elderly: See [Usage and Dosage] and [Precautions].

1. Patients with reversible obstructive airway disease should avoid the use of selective and non-selective beta-blockers unless absolutely necessary. 2. Since the plasma concentrations achieved at inhaled doses are very low, clinically significant drug interactions are unlikely to occur. When using known strong CYP3A4 inhibitors (such as diconazole and ritonavir) at the same time, attention should be paid to the possibility of increased systemic exposure due to the use of fluticasone propionate.

Store below 30°C.

50ug/500ug/soak

18 months.