Seretide Multidisc, 50 mcg+500 mcg/dose 60 doses

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

Pharmacodynamics
The drug Seretide 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 the release from human lung tissue of mast cell mediators such as histamine, LT and PG D₂.

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 cortical hormone secretion has gradually improved despite prior and current intermittent use of oral steroids. This indicates recovery of adrenal function with inhaled use of fluticasone propionate.

In long-term 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 Multidisk 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. Bioavailability from the gastrointestinal tract 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 of inhalation powder contains:

Active substances:

salmeterol xinaphoate 72.5 µg (in terms of salmeterol 50 µg),

fluticasone propionate (micronized) 500 μg;

Auxiliary substances:

Lactose monohydrate, up to 12.5 mg

How to take, the dosage

For optimal effect, the drug should be used regularly, even in the absence of clinical symptoms of bronchial asthma and COPD. Determining the duration of therapy and changing the dose of the drug is possible only on the doctor’s recommendation. The patient should be prescribed the formulation of Seretide Multidisc which contains the dose of fluticasone propionate corresponding to the severity of his 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. For 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 reduction of the corticosteroid dose without loss of bronchial asthma control.

Inhaled, intended for inhalation only.

Recommended doses

Adults and children 12 years and older: 1 inhalation (50 µg salmeterol and 100 µg fluticasone propionate) 2 times daily, or 1 inhalation (50 µg salmeterol and 250 µg fluticasone propionate) 2 times daily, or 1 inhalation (50 µg salmeterol and 500 µg fluticasone propionate) 2 times daily.

In adults over 18 years of age, when doubling the dose with any formulation of Seretide Multidisc for up to 14 days, the same safety and tolerability is maintained as with regular use of this combination of 1 inhalation 2 times daily. The dose may be doubled when patients require additional short-term (up to 14 days) inhaled corticosteroid therapy, as described in some bronchial asthma treatment guidelines.

Children 4 years and older: 1 inhalation (50 µg salmeterol and 100 µg fluticasone propionate) 2 times daily.

There are currently no data on the use of Seretide Multidisc in children under 4 years of age.

CROPD

In adult patients, the maximum recommended dose is 1 inhalation (50 mcg salmeterol and 500 mcg fluticasone propionate) 2 times daily.

Patient special groups

There is no need to reduce the dose in elderly patients or in patients with renal or hepatic impairment.

Interaction

Because of the risk of bronchospasm, concomitant use of selective and nonselective β-adrenoblockers should be avoided unless they are extremely necessary for the patient.

In normal situations, inhalation of fluticasone propionate is accompanied by low plasma concentrations due to intensive metabolism during the “first” passage and high systemic clearance under the influence of cytochrome P450 system CYP3A4 isoenzyme in the intestine and liver. Because of this, clinically significant interactions involving fluticasone propionate are unlikely.

The study of drug interactions has shown that ritonavir (a highly active CYP3A4 isoenzyme inhibitor) can cause a dramatic increase in plasma concentrations of fluticasone propionate, which results in significantly lower serum cortisol concentrations.

There have been reports of clinically significant drug interactions in patients who received fluticasone propionate and ritonavir simultaneously. These interactions have caused side effects such as Cushing’s syndrome and depressed adrenal function. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided unless the potential benefit to the patient outweighs 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 increased plasma concentrations of fluticasone propionate.

Xanthine derivatives, GCS and diuretics increase the risk of hypokalemia (especially in patients with exacerbation of bronchial asthma, with hypoxia).

MoA inhibitors and tricyclic antidepressants increase the risk of adverse cardiovascular events.

Compatible with cromoglycic acid.

Special Instructions

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 drugs Seretide® and Seretide® Multidisc are not intended to relieve acute symptoms, as a fast-acting, short-acting inhaled bronchodilator (such as salbutamol) should be used in these cases. Patients should be informed that they should always have a medication on hand to relieve acute symptoms.

Salmeterol/fluticasone propionate can be used for initial maintenance therapy in patients with persistent bronchial asthma (daily onset of symptoms or daily use of an attack control agent) when corticosteroids are indicated and the approximate dosage is determined.

The more frequent use of short-acting bronchodilators to relieve symptoms is indicative of worsening disease control, and in these situations, the patient should consult a physician.

The sudden and worsening worsening of bronchospastic syndrome control is potentially life-threatening, and in these situations, the patient should also see a physician. It is possible that the doctor will prescribe a higher dose of GCS. If the dose of Seretide® and Seretide® Multidisc does not provide adequate disease control, the patient should also see a physician, who may prescribe additional GCS and, if the exacerbation is caused by an infection, antibiotics.

Because of the risk of an exacerbation, treatment with Seretide® and Seretide® Multidisc should not be stopped abruptly, the dose must be reduced gradually with medical monitoring.

Any inhaled GCS can cause systemic effects, especially with long-term use at high doses; however, it should be noted that these symptoms are much less likely to occur than with treatment with oral GCS. Possible systemic effects include inhibition of adrenal function, growth retardation in children and adolescents, decreased bone mineral density, development of cataracts and glaucoma. With this in mind, the dose of inhaled GCS should be titrated to the minimum to maintain effective control.

In emergency and routine situations that may cause stress, always be aware of the possibility of adrenal suppression and be prepared to use GCS.

In resuscitation or surgical procedures, a determination of the degree of adrenal insufficiency is required.

It is recommended that the height of children who receive long-term inhaled GCS therapy be measured regularly.

Some patients may be more sensitive to the effects of inhaled GCS than most patients.

Because of potential adrenal depression, patients transferred from oral GKS to inhaled therapy with fluticasone propionate should be treated with extreme caution and their adrenal function monitored regularly. Allergic reactions (e.g., allergic rhinitis, eczema) that were previously suppressed by systemic GCS may occur when transferring patients from systemic GCS to inhaled therapy. In these situations, symptomatic treatment with antihistamines and/or topical agents, including GCS for topical use, is recommended.

After initiation of treatment with inhaled fluticasone propionate, systemic GCS should be withdrawn gradually, and these patients should have a special chart indicating the possible need for additional GCS administration in stressful situations.

In patients with exacerbation of bronchial asthma, hypoxia, plasma K+ concentrations should be monitored.

There have been very rare reports of increased blood glucose levels, and this should be kept in mind when prescribing the combination of salmeterol with fluticasone propionate in 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.

Side effects

The drugs Seretide and SeretideMultidisk contain salmeterol and fluticasone propionate, and therefore one should expect that the drugs may cause side effects characteristic of these components. There is no evidence that concomitant use of salmeterol and fluticasone propionate causes additional side effects.

May cause paradoxical bronchospasm. In this case, a short-acting inhaled bronchodilator should be used immediately, the drug should be discontinued, and alternative therapy should be started if indicated.

Salmeterol: pharmacological side effects of beta2-adrenoceptor agonist such as tremor, palpitations and headache, hypokalemia have been described, which are usually transient and subside as salmeterol therapy continues.

In sensitive patients, arrhythmias (including atrial fibrillation, supraventricular tachycardia, and extrasystoles) may occur.

There have been reports of arthralgia, nervousness, abdominal pain, nausea, vomiting, and hypersensitivity reactions including skin rash, peripheral edema, and angioedema.

In cases of irritation of the mucous membranes of the oropharynx and changes in taste sensation (dysgeusia) have been described.

Published reports of cases of painful muscle cramps and very rare cases of hyperglycemia.

Fluticasone propionate: coarsening or hoarseness of the voice and candidiasis (thrush) of the mouth and throat may occur in some patients.

Skin hypersensitivity reactions have been described. Hypersensitivity reactions have also been reported in the form of angioedema (mainly swelling of the face and oropharynx), respiratory disorders (mainly dyspnea and/or bronchospasm) and anaphylactic reactions.

The severity and frequency of voice coarsening and candidiasis can be reduced by rinsing the mouth with water after inhalation. Symptomatic candidiasis can be treated with topical antifungal medications while continuing therapy with SeretidilisMultidisc.

A very rare occurrence of anxiety, sleep disturbance and behavioral disorders, including hyperactivity and irritability (mostly in children); hyperglycemia have been reported.

Theoretically it is possible to develop systemic reactions including Cushing’s syndrome or Cushingoid symptoms, depressed adrenal function, growth retardation in children and adolescents, decreased bone mineral density, cataracts and glaucoma.

Long-term use of doses of the combination of salmeterol and fluticasone propionate that exceed the approved doses may result in significant inhibition of adrenal cortical function. There are very rare reports of acute adrenal crisis, which occurred mainly in children who received higher than authorized doses of this combination for a long time (several months or years); symptoms of adrenal crisis included hypoglycemia accompanied by decreased level of consciousness and/or seizures.

Overdose

Symptoms: objective and subjective symptoms of salmeterol overdose include tremor, headache, and tachycardia. Inhalation of doses of fluticasone propionate higher than recommended may cause temporary suppression of the hypothalamic-pituitary-adrenal system. This usually does not require any emergency action, because in most cases normal adrenal function is restored within a few days.

In prolonged inhalation of excessively high doses of Seretidi Seretid Multidisc may result in significant adrenal suppression. There are rare reports in the literature of acute adrenal crisis, which occurs predominantly in children receiving excessively high doses over a long period of time (several months or years); acute adrenal crisis manifests as 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 the drug fluticasone propionate.

Treatment: The antidotes are cardioselective β-adrenoblockers. If Seretide and Seretide Multidisc are to be stopped due to an overdose of its constituent salmeterol, the patient should be prescribed an appropriate replacement GCS.

Patients should be aware that Seretide and Seretide Multidisc should not be taken in doses higher than recommended. It is important to regularly evaluate the effectiveness of therapy and reduce the dose to the lowest effective dose, which is the dose that provides effective control of disease symptoms.

In chronic overdose, monitoring of adrenal cortical reserve function is recommended.

Pregnancy use

Pregnant and lactating women should only prescribe the drug if the expected benefit to the mother outweighs any possible risk to the fetus or child.

Similarities