Seretide Multidisc, 50 mcg+250 mcg/dose 60 doses

The drug Seretide Multidisc has anti-asthmatic, bronchodilator, anti-inflammatory action.

Pharmacodynamics

The drug Seretid Multidisc is a combined preparation that contains salmeterol and fluticasone propionate, which have different mechanisms of action. Salmeterol prevents bronchospasm, fluticasone propionate improves pulmonary function and prevents exacerbations. The drugs may be an alternative for patients who simultaneously receive a β₂ adrenoreceptor agonist and an inhaled GCS.

Salmeterol is a selective long-acting (up to 12 hours) β₂ adrenoreceptor agonist that has a long side chain that binds to the outer domain of the receptor.

The pharmacological properties of salmeterol provide protection against histamine-induced bronchoconstriction and longer bronchodilation (lasting at least 12 hours) than short-acting β₂-adrenoreceptor agonists. The onset of bronchodilator effect is within 10-20 minutes. Salmeterol is a strong and long-acting inhibitor of mast cell mediators such as histamine, LT and PG D₂ release from human lung tissue.

Salmeterol inhibits the early and late phases of response to inhaled allergens; the latter lasts for more than 30 h after administration of 1 dose, a time when the bronchodilator effect is no longer present. A single dose of salmeterol attenuates bronchial hyperresponsiveness. This indicates that salmeterol, in addition to its bronchodilator activity, has an additional action, the clinical significance of which has not been definitively established. This mechanism of action is different from the anti-inflammatory effect of GCS. In therapeutic doses, salmeterol has no effect on CCC.

Fluticasone propionate belongs to the group of GCS for local use and when administered by inhalation in the recommended doses it has a pronounced anti-inflammatory and anti-allergic effect in the lungs, which leads to reduction of clinical symptoms and decreases the frequency of exacerbations of diseases accompanied by airway obstruction. It restores the patient’s response to bronchodilators, allowing to reduce the frequency of their use. The action of fluticasone propionate is not accompanied by the adverse reactions typical for systemic GCS.

Long-term use of inhaled fluticasone propionate at maximum recommended doses keeps daily adrenal hormone secretion within normal limits in both adults and children. After switching patients receiving other inhaled GCSs to fluticasone propionate, daily adrenal hormone secretion gradually improves despite prior and current intermittent use of oral steroids.

This indicates recovery of adrenal function with inhaled fluticasone propionate. With prolonged use of fluticasone propionate, adrenal reserve function also remains within normal limits, as indicated by a normal increase in cortisol production in response to appropriate stimulation (note that residual decrease in adrenal reserve caused by prior therapy may persist for a long time).

A study of 318 adult patients with persistent bronchial asthma showed that when using a doubled dose of Seretide and Seretide Multidisc for 14 days (regardless of the dose of components in the drug) there was a slight increase in the frequency of adverse events associated with the action of β-adrenomimetic (tremor – 1 patient (1%), 0 patients – at the usual dose; palpitations – 6 patients (6%), 1 patient (

Pharmacokinetics

. When co-inhaled, salmeterol and fluticasone propionate do not affect the pharmacokinetics of each other, so the pharmacokinetic characteristics of each component of Seretide Multidisc can be considered separately.

Even though the plasma concentrations of salmeterol and fluticasone propionate are very low, interactions with other substrates and CYPZA4 isoenzyme inhibitors cannot be excluded.

Salmeterol: acts locally in pulmonary tissue, so its plasma content does not correlate with the therapeutic effect. Data on its pharmacokinetics are very limited due to technical problems: when inhaled at therapeutic doses, its C_max in plasma is extremely low (about 200 pg/mL and below). After repeated inhalations of salmeterol xinaphoate, hydroxynaphthoic acid, C_ss of which is about 10 pg/mL, can be detected in the blood. These concentrations are 1000 times lower than the equilibrium levels observed in toxicity studies.

Fluticasone propionate: The absolute bioavailability of inhaled fluticasone propionate in healthy subjects varies depending on the inhaler used (when using salmeterol/fluticasone propionate with a metered dose inhaler aerosol, it is 5.3% of the nominal dose). In patients with bronchial asthma and COPD, lower plasma concentrations of fluticasone propionate are observed. Systemic absorption occurs predominantly through the lungs, and it is faster at first, but then slows down.

A portion of the inhaled dose may be swallowed, but this portion contributes minimally to systemic absorption due to the drug’s low water solubility and due to its presystemic metabolism.

The gastrointestinal bioavailability is less than 1%. With increasing inhalation dose a linear increase in plasma concentration of fluticasone propionate is observed. The distribution of fluticasone propionate is characterized by rapid plasma clearance (1150 mL/min), a large V_ss (approximately 300 L), and a final T_1/2 of approximately 8 h. Fluticasone propionate has a relatively high degree of binding to plasma proteins (91%). It is rapidly eliminated from the blood, mainly as a result of metabolism by CYP3A4 isoenzyme to inactive carboxyl metabolite.

The renal clearance of unchanged fluticasone propionate is negligible (

Extracted through the gastrointestinal tract, mainly as a hydroxylated metabolite.

Indications

The treatment of bronchial asthma in patients who are indicated for combination therapy with a long-acting β2-adrenomimetic and an inhaled corticosteroid:

Active ingredient

Composition

1 dose contains:

salmeterol (in the form of xinaphoate) 50 µg,

fluticasone propionate 250 µg;

Associated substances:

Lactose monohydrate, up to 12.5 mg.

How to take, the dosage

Seretide Multidisc is intended for inhalation only. For optimal effect, the drug should be used regularly, even in the absence of clinical symptoms of bronchial asthma and COPD.

The course of treatment and change of dose is determined by the doctor individually. The patient should be prescribed Seretide Multidisc in a dosage form that contains a dose of fluticasone propionate corresponding to the severity of the disease.

If a patient fails to achieve adequate disease control with inhaled corticosteroid monotherapy, switching to combination therapy with salmeterol and fluticasone propionate at an equivalent corticosteroid dose may result in improved bronchial asthma control.

In those patients in whom inhaled corticosteroid monotherapy provides adequate bronchial asthma control, switching to inhaled therapy with a combination of salmeterol and fluticasone propionate may allow a lower dose of corticosteroid without loss of bronchial asthma control.

The recommended doses for adults and children 12 years of age and older are 1 inhalation (50 µg salmeterol and 100 µg fluticasone propionate) 2 times/day, or 1 inhalation (50 µg salmeterol and 250 µg fluticasone propionate) 2 times/day, or 1 inhalation (50 µg salmeterol and 500 µg fluticasone propionate) 2 times/day.
In adults over 18 years of age the same safety and tolerability is maintained for 14 days when doubling the dose with any form of Seretide Multidisk as with the regular use of this combination of 1 inhalation 2 times/day. The dose may be doubled when patients require additional short-term (up to 14 days) inhaled GCS therapy as described in some bronchial asthma treatment guidelines.
For children aged 4 years and older, 1 inhalation (50 µg salmeterol and 100 µg fluticasone propionate) 2 times/day.
In COPD for adults, the maximum recommended dose is 1 inhalation (50 µg salmeterol and 500 µg fluticasone propionate) 2 times/day.

Interaction

Because of the risk of bronchospasm, the use of selective and nonselective beta-adrenoblockers should be avoided unless really necessary and justified.

In diseases accompanied by reversible airway obstruction, both nonselective and cardioselective beta-adrenoblockers should be avoided unless really necessary and justified. When fluticasone propionate is administered by inhalation, its plasma concentrations are low due to intensive metabolism during “first passage” through the liver under the influence of CYP3A4 isoenzyme and high systemic clearance.

This makes clinically significant interaction involving fluticasone propionate unlikely. Caution should be exercised when concomitant use of known CYP3A4 inhibitors and fluticasone propionate, because in such situations the plasma content of the latter may increase.

Ritonavir (a highly active CYP3A4 isoenzyme inhibitor) can cause a significant increase in plasma concentrations of fluticasone propionate; as a consequence, serum cortisol concentrations are significantly reduced. There have been reports of clinically significant drug interactions in patients who simultaneously received fluticasone propionate and ritonavir, which was manifested by the development of Icenko-Cushing’s syndrome and depression of adrenal function.

Bearing this in mind, concomitant use of fluticasone propionate and ritonavir should be avoided unless the potential benefit to the patient from the combined therapy exceeds the risk of systemic side effects of GCS.

Other CYP3A4 isoenzyme inhibitors cause negligible (erythromycin) and minor (ketoconazole) increases in plasma fluticasone propionate with little or no reduction in serum cortisol concentrations. Despite this, caution is recommended when concomitant use of fluticasone propionate and strong CYP3A4 inhibitors (e.g., ketoconazole), since such combinations do not exclude the possibility of increasing plasma concentrations of fluticasone propionate.

When used concomitantly with the preparation Seretide® Multidisk xanthine derivatives, GCS and diuretics increase the risk of hypokalemia (especially in patients with exacerbation of bronchial asthma, with hypoxia); MAO inhibitors and tricyclic antidepressants increase the risk of cardiovascular side effects. Seretide Multidisc is compatible with cromoglycic acid.

Special Instructions

Seretide Multidisc is intended for long-term treatment of the disease, not for seizure management. Patients should be prescribed short-acting inhaled bronchodilators (e.g., salbutamol) to control the attacks, and patients are recommended to have them with them at all times. If paradoxical bronchospasm develops, a short-acting inhaled bronchodilator should be used immediately, Seretide® Multidisc should be discontinued and alternative therapy should be initiated if indicated.

The treatment of bronchial asthma is recommended in stages, monitoring the patient’s clinical response to treatment and lung function. The patient should be taught how to use the inhaler correctly. The severity and frequency of coarsening of the voice and candidiasis can be reduced by rinsing the mouth with water after inhalation of Seretide Multidisc. If candidiasis occurs, antifungal medications for topical use are prescribed while continuing therapy with Seretide Multidisc.

In elderly persons and patients with renal insufficiency or impaired liver function, no dose reduction is required. The drug can be used for initial maintenance therapy in patients with persistent bronchial asthma (daily occurrence of symptoms or daily use of agents for relief of attacks) if there are indications for prescription of GCS and when determining the approximate dosage.

The more frequent use of short-acting bronchodilators to relieve symptoms indicates worsening disease control, and in these situations the patient should consult a physician. A sudden and progressive worsening of bronchospastic syndrome control is potentially life-threatening. A physician’s monitoring is necessary in such situations.

If the dose of Seretide Multidisc used does not adequately control the disease, an additional prescription of GCS may be necessary, and if the exacerbation is caused by an infection, antibiotics are prescribed. Because of the risk of exacerbation, abrupt withdrawal of Seretide Multidisc should be avoided and the dose of the drug should be reduced gradually under medical supervision. When using any inhaled GCS it is possible to develop systemic effects (inhibition of adrenal function, growth retardation in children and adolescents, reduced bone mineral density, cataracts and glaucoma), especially with long-term use at high doses, but the probability of these effects is much lower than with treatment with oral forms of GCS. With this in mind, the dose of inhaled GCS should be titrated to the minimum dose that maintains effective control. In emergency and routine stress situations, we should always remember about the possibility of adrenal function depression and the need for GCS.

In resuscitation or surgical procedures, a determination of the degree of adrenal insufficiency is required. Some patients may have individual high sensitivity to GCS for inhalation. Due to possible adrenal insufficiency, special caution should be exercised and adrenal function parameters should be regularly monitored when transferring patients who took oral GCS to treatment with fluticasone propionate for inhalation.

Allergic reactions (e.g., allergic rhinitis, eczema) which were previously suppressed by systemic GCS may occur when transferring patients from systemic GCS to inhaled therapy. In such situations, symptomatic treatment with antihistamines and/or topical agents (including GCS for topical use) is recommended. Withdrawal of systemic GCS against the background of inhaled fluticasone propionate should be carried out gradually. Patients should carry a card indicating that they may need to take additional GCS in various stressful situations.

Pediatric use: It is recommended to monitor the growth dynamics of children who receive long-term inhaled GCS therapy. There are currently no data on the use of Seretide Multidisc in children under 4 years of age.

Control of laboratory parameters: in patients with exacerbation of bronchial asthma, hypoxia it is necessary to monitor the concentration of potassium in plasma. There are very rare reports of elevated blood glucose levels; this should be kept in mind when prescribing the combination of salmeterol with fluticasone propionate to diabetic patients.

Contraindications

Hypersensitivity to the components of the drug Seretide Multidisc; children under 4 years of age.

With caution: Pulmonary tuberculosis, fungal, viral or bacterial respiratory infections, thyrotoxicosis, pheochromocytoma, diabetes mellitus, uncontrolled hypokalemia, idiopathic hypertrophic subaortic stenosis, uncontrolled arterial hypertension, arrhythmias, prolongation of QT interval on ECG, CHD, hypoxia of various genesis, cataracts, glaucoma, hypothyroidism, osteoporosis, pregnancy, lactation.

Overdose

Symptoms: tremor, headache and tachycardia caused by the action of salmeterol; temporary suppression of the hypothalamic-pituitary-adrenal system, which is caused by the action of fluticasone. Inhalation of Seretide Multidisk at excessively high doses for a long time may cause marked suppression of adrenal function.

There are rare reports of acute adrenal crisis, which occurs mainly in children receiving Seretide Multidisc in excessively high doses for a long time (several months or years). Acute adrenal crisis is manifested by hypoglycemia accompanied by confusion and/or seizures. Situations that may serve as triggers for acute adrenal crisis include trauma, surgery, infection, or a rapid decrease in the dose of fluticasone propionate in Seretide Multidisc.

Treatment: Salmeterol-induced symptoms should be managed by administration of an antidote, a cardioselective beta-adrenoblocker. In cases where withdrawal of Seretide Multidisc is required due to an overdose of its constituent salmeterol, the patient should be prescribed an appropriate replacement GCS.

The symptoms caused by fluticasone propionate usually do not require emergency therapy because in most cases normal adrenal function is restored within a few days. In chronic overdose, monitoring of adrenal cortical reserve function is recommended.

In order to avoid overdose, patients should not use Seretide Multidisc in doses higher than recommended. Regular evaluation of the effectiveness of therapy and reducing the dose of Seretide Multidisc to the minimum level that provides effective control of disease symptoms is important.

Pregnancy use

In pregnancy and during lactation (breastfeeding), Seretide may be administered only if the anticipated benefit to the mother outweighs any possible risk to the fetus or child.

Similarities