Seretide Diskus 50mcg/250mcg 60 doses

Instructions Seretide Diskus 50mcg/250mcg 60 doses

Composition

active ingredients: salmeterol xinafoate, fluticasone propionate;

1 dose of the drug contains 50 mcg of salmeterol (in the form of salmeterol xinafoate) micronized and 100 mcg of fluticasone propionate (micronized) or 50 mcg of salmeterol (in the form of salmeterol xinafoate) micronized and 250 mcg of fluticasone propionate (micronized), or 50 mcg of salmeterol (in the form of salmeterol xinafoate) micronized and 500 mcg of fluticasone propionate (micronized);

excipient: lactose monohydrate.

Dosage form

Inhalation powder, metered.

Main physicochemical properties: white or almost white powder.

Pharmacotherapeutic group

Antiasthmatic agents for inhalation use. Adrenergic agents in combination with other antiasthmatic agents. Salmeterol and fluticasone. ATX code R03A K06.

Pharmacological properties

Pharmacodynamics: Seretide Diskus contains salmeterol and fluticasone propionate, which have different mechanisms of action.

Salmeterol

Salmeterol is a long-acting (12 hours) selective b2-adrenoceptor agonist that has a long side chain linked to the outer domain of the receptor.

Salmeterol provides longer-lasting bronchodilation (at least 12 hours) than recommended doses of traditional short-acting b2-adrenergic agonists.

Fluticasone propionate

Fluticasone propionate, when used by inhalation at recommended doses, has a pronounced glucocorticoid anti-inflammatory effect in the lungs, which leads to a reduction in clinical symptoms and the frequency of exacerbations of bronchial asthma without the occurrence of adverse reactions observed with systemic use of corticosteroids.

Pharmacokinetics

When salmeterol and fluticasone propionate are used together by inhalation, the pharmacokinetics of each component remain the same as when these components are used separately, therefore their pharmacokinetics are presented separately.

Salmeterol

Salmeterol acts locally in the lung tissue, so its amount in the blood plasma does not correlate with the therapeutic effect. In addition, data on the pharmacokinetics of salmeterol are limited, as there are technical difficulties in determining the very low plasma concentrations of the drug (approximately 200 pg/ml and less) after its inhalation use at therapeutic doses.

Fluticasone propionate

The absolute bioavailability of fluticasone propionate after inhalation in healthy volunteers is approximately 5-11% of the nominal dose, depending on the inhalation device used. In patients with bronchial asthma, lower levels of systemic exposure are observed with inhaled fluticasone propionate. Systemic absorption occurs mainly in the lungs, initially rapidly, then slowing down. Part of the inhaled dose may be swallowed, but its systemic effect is minimal due to the poor solubility of fluticasone propionate in water and extensive first-pass metabolism in the liver. The bioavailability of fluticasone propionate when absorbed from the gastrointestinal tract is less than 1%. There is a linear increase in the concentration of fluticasone propionate in the blood plasma with increasing inhaled dose of the drug. The distribution of fluticasone propionate is characterized by a high plasma clearance (1150 ml/min), a large volume of distribution (approximately 300 l) and a terminal half-life of approximately 8 hours. The degree of binding to plasma proteins is relatively high (91%). Fluticasone propionate is rapidly eliminated from the systemic circulation, mainly by metabolism to an inactive carboxyl metabolite by the cytochrome P450 enzyme CYP3A4. Other unidentified metabolites are excreted in the feces. Renal clearance of fluticasone propionate is very low, with less than 5% of the dose excreted in the urine, mainly as the metabolite. The majority of the dose is excreted in the feces as metabolites and unchanged drug.

Indication

Bronchial asthma

Regular treatment of bronchial asthma in patients for whom combination therapy with a long-acting beta2-adrenomimetic and an inhaled corticosteroid is indicated:

patients with insufficient disease control on continuous monotherapy with an inhaled corticosteroid with periodic use (as needed) of a short-acting beta2-adrenomimetic;

patients with adequate disease control on treatment with an inhaled corticosteroid and a long-acting beta2-adrenomimetic.

Chronic obstructive pulmonary disease

Maintenance therapy of chronic obstructive pulmonary disease (COPD) in patients with FEV1 < 60% of predicted value (before bronchodilator inhalation) and a history of repeated exacerbations, in whom severe symptoms of the disease persist despite regular bronchodilator therapy.

Contraindication

Hypersensitivity to any of the components of the drug.

Interaction with other medicinal products and other types of interactions

Concomitant use with medicinal products containing other b-adrenergic drugs may have a potential additive effect.

Fluticasone propionate

Under normal conditions, low plasma concentrations of fluticasone propionate are achieved after inhalation due to extensive first-pass metabolism and high systemic clearance of the drug mediated by cytochrome CYP3A4 in the liver and intestine. Therefore, the likelihood of clinically significant drug interactions mediated by fluticasone propionate is very low.

Drug interaction studies with intranasal fluticasone propionate in healthy volunteers have shown that ritonavir (a potent inhibitor of cytochrome CYP3A4) can significantly increase the plasma concentration of fluticasone propionate, which will lead to a significant decrease in serum cortisol concentrations. No such information is available for inhaled fluticasone propionate, but a marked increase in serum fluticasone propionate levels is expected. Cushing's syndrome and adrenal suppression have been reported. Concomitant use should be avoided unless the benefit outweighs the increased risk of systemic glucocorticoid side effects.

In a small study in healthy volunteers, fluticasone propionate exposure was increased by 150% after a single inhalation with the less potent CYP3A inhibitor ketoconazole, resulting in a greater reduction in plasma cortisol levels compared to fluticasone propionate alone. Co-administration with other potent CYP3A inhibitors such as itraconazole, cobicistat-containing products, and moderate CYP3A inhibitors such as erythromycin is expected to increase systemic exposure to fluticasone propionate and the risk of systemic adverse reactions.

Such combinations should be avoided unless the expected benefit outweighs the potential increased risk of systemic adverse reactions associated with corticosteroids; in such cases, patients should be monitored for the development of systemic adverse events.

Salmeterol

Strong CYP3A4 inhibitors

Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 mcg inhaled twice daily) in 15 healthy volunteers for 7 days resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC). This may lead to an increase in other systemic effects of salmeterol treatment (e.g. QT prolongation and palpitations) compared to salmeterol or ketoconazole alone (see section 4.4).

There were no clinically significant effects on blood pressure, heart rate, blood glucose, or blood potassium. Co-administration with ketoconazole did not increase the half-life of salmeterol or the accumulation of salmeterol with repeated dosing.

Concomitant use with ketoconazole should be avoided unless the benefit outweighs the potential risk of systemic adverse effects with salmeterol. There is likely to be a similar risk of interaction with other strong CYP3A4 inhibitors (e.g. itraconazole, telithromycin, ritonavir).

Moderate CYP3A4 inhibitors

Co-administration of erythromycin (500 mg orally 3 times a day) and salmeterol (50 mcg inhaled 2 times a day) in 15 healthy volunteers for 6 days resulted in a small and statistically insignificant increase in plasma salmeterol exposure (1.4-fold Cmax and 1.2-fold AUC). Co-administration with erythromycin was not associated with any adverse effects.

Application features

Seretide Diskus is not a medicine for the relief of acute symptoms when rapid-acting and short-acting bronchodilators are required. The patient should be advised to carry a reliever medicine with them at all times.

Seretide Diskus should not be initiated during an exacerbation of the disease, in case of significant or acute deterioration of the patient's condition and course of the disease.

Serious asthma-related adverse reactions and exacerbations may occur during treatment with Seretide Diskus. Patients should be advised to continue treatment but to seek medical advice if symptoms remain uncontrolled or worsen after starting treatment with Seretide Diskus.

Increased use of short-acting bronchodilators to relieve asthma symptoms indicates worsening asthma control. In this situation, the patient should consult a doctor.

Sudden and progressive deterioration in asthma control is potentially life-threatening and the patient should be evaluated by a physician. The dose of corticosteroids may need to be increased. The patient should also be evaluated by a physician if the prescribed dose of Seretide Diskus does not provide adequate control of asthma symptoms.

The issue of additional corticosteroids for patients with asthma or COPD should be addressed.

Due to the risk of exacerbation of asthma, treatment with Seretide Diskus should not be stopped abruptly, the dose should be reduced gradually, under the supervision of a doctor. Reduction of therapeutic doses should be carried out under the supervision of a doctor. In patients with chronic obstructive pulmonary disease, discontinuation of treatment may also cause decompensation of symptoms, therefore it should be carried out under the supervision of a doctor.

As with any inhaled corticosteroid, Seretide Diskus should be used with caution in patients with active or latent pulmonary tuberculosis, fungal, viral or other respiratory tract infections. In such cases, appropriate treatment should be initiated immediately, if necessary.

Cardiovascular effects, such as increases in systolic blood pressure and heart rate, may be observed with all sympathomimetic drugs, especially at high doses. Therefore, the drug should be used with caution in patients with cardiovascular disease.

Seretide Diskus, when used in high therapeutic doses, may occasionally cause cardiac arrhythmias, such as supraventricular tachycardia, extrasystoles or atrial fibrillation, and a mild, transient decrease in serum potassium. Therefore, the drug should be used with caution in patients with cardiac arrhythmias, diabetes mellitus, thyrotoxicosis, patients with uncorrected hypokalemia or patients prone to low serum potassium.

Very rarely, increases in blood glucose levels have been reported (see section 4.8), and this should be taken into account when prescribing the drug to patients with a history of diabetes.

As with other inhaled medications, paradoxical bronchospasm with immediate increase in dyspnea after inhalation may occur. Appropriate treatment with a short-acting inhaled bronchodilator should be initiated immediately. Seretide Diskus should be discontinued immediately, the patient assessed and, if necessary, alternative therapy instituted.

Pharmacological side effects of β2-agonist treatment, such as tremor, palpitations and headache, have been reported, but these are transient and decrease with regular treatment (see section “Adverse reactions”).

Seretide Diskus contains 12.5 mg of lactose monohydrate per dose delivered. This amount does not usually cause reactions in people with lactose intolerance. Lactose contains small amounts of milk protein, which may cause allergic reactions.

Systemic effects may occur with inhaled corticosteroids, especially at high doses, over a long period of time. These are much less likely to occur than with oral corticosteroids (see section 4.8). Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineralization, cataracts and glaucoma, and less commonly, mental and behavioural changes including psychomotor hyperactivity, sleep disturbances, agitation, depression or aggression (predominantly in children). It is therefore important that the patient's condition is reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest effective dose at which asthma symptoms are controlled.

Long-term treatment of patients with high doses of inhaled corticosteroids may cause adrenal suppression and acute adrenal crisis. Isolated cases of adrenal suppression and acute adrenal crisis have been reported with fluticasone propionate doses of 500 mcg and 1000 mcg/day. Factors that may precipitate acute adrenal crisis include trauma, surgery, infection or rapid dose reduction. Symptoms are usually vague and may include anorexia, abdominal pain, weight loss, fatigue, headache, nausea, vomiting, hypotension, decreased level of consciousness, hypoglycaemia and convulsions. Additional systemic corticosteroids should be considered during periods of stress or during surgery.

The use of inhaled fluticasone propionate should minimise the need for oral steroids, but patients who are transferred from oral steroids for a period of time may still be at risk of developing impaired adrenal reserve. Therefore, such patients should be treated with special care and with regular monitoring of adrenal function. Patients who have used high doses of corticosteroids as emergency treatment in the past are also at risk. The possibility of residual insufficiency should always be borne in mind in emergency care and in potentially stressful situations and the need for corticosteroids should be considered. Special advice may be required before certain procedures to assess the degree of adrenal insufficiency.

When starting inhaled fluticasone propionate, withdrawal of systemic treatment should be gradual, and patients should be advised to carry a steroid alert card at all times, indicating the possible need for additional therapy in a stressful situation.

Ritonavir use may significantly increase the plasma concentrations of fluticasone propionate. Therefore, concomitant use should be avoided unless the potential benefit outweighs the risk of systemic corticosteroid adverse reactions. The risk of systemic adverse reactions is also increased when fluticasone propionate is used concomitantly with other strong CYP3A inhibitors (see section 4.5).

Pneumonia in patients with COPD

An increased incidence of pneumonia, including pneumonia requiring hospitalization, has been observed in patients with COPD who are taking inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid doses, but this has not been conclusively demonstrated in all studies.

There is no convincing clinical evidence that different classes of inhaled corticosteroids are associated with different risks of pneumonia. Clinicians should be alert to the possibility of pneumonia in patients with COPD, as the clinical features of such infections overlap with those of COPD exacerbations. Risk factors for pneumonia in patients with COPD include smoking, older age, low body mass index (BMI), and severe COPD.

Concomitant use with systemic ketoconazole significantly increases systemic exposure to salmeterol, which may lead to an increased incidence of systemic effects (e.g. QT prolongation and palpitations). Therefore, concomitant use with ketoconazole and other strong CYP3A inhibitors should be avoided unless the benefit outweighs the potential increased risk of systemic adverse reactions from salmeterol treatment (see section 4.5).

Vision impairment

Visual impairment may occur with systemic and topical corticosteroids. If a patient presents with symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist for evaluation of possible causes, which may include cataracts, glaucoma, or rare conditions such as central serous chorioretinopathy, which have been reported with systemic and topical corticosteroids.

Children

Children and adolescents under 16 years of age treated with high doses of fluticasone propionate (usually ≥ 1000 mcg/day) are at particular risk of developing systemic effects. Systemic effects are usually caused by treatment with the drug at high doses for a long time. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, acute adrenal crisis, growth retardation in children and adolescents, decreased bone mineralization, cataracts and glaucoma, and less commonly, mental disorders and behavioral changes, including psychomotor hyperactivity, sleep disorders, agitation, depression or aggression.

It is recommended that growth be monitored regularly in children receiving inhaled corticosteroids for long periods of time. The dose of inhaled corticosteroids should be reduced to the lowest effective dose to control asthma symptoms.

Use during pregnancy or breastfeeding

Fertility

There are no data on the effects on human fertility. Animal studies have not shown any effect of salmeterol or fluticasone propionate on fertility.

Pregnancy

Data on use in human pregnancy are limited. Seretide Diskus should be used during pregnancy only if the expected benefit to the mother outweighs any risk to the foetus. Seretide Diskus exposure during pregnancy (more than 1000 exposures) has not been associated with any adverse effects on embryonal development or foetal malformations. A retrospective epidemiological study has not shown an increased risk of major birth defects following exposure to fluticasone propionate during the first trimester of pregnancy compared with other inhaled corticosteroids.

In animal studies, reproductive toxicity was observed following administration of a β2-adrenoceptor agonist and a glucocorticosteroid.

For the treatment of pregnant women, the lowest effective doses of fluticasone propionate are prescribed to maintain adequate control of asthma symptoms.

Breast-feeding

There are no data on the concentration of the drug in human breast milk. Studies have shown that salmeterol and fluticasone propionate and their metabolites are excreted in the breast milk of rats. A risk to the infant from breastfeeding during maternal treatment with Seretide Diskus cannot be excluded. Seretide Diskus should be used during breastfeeding only if the expected benefit to the mother outweighs any possible risk to the child.

Ability to influence reaction speed when driving vehicles or other mechanisms

Specific studies of the effect of Seretide Diskus on this activity have not been conducted, but given the pharmacology of both drugs, it can be assumed that there is no effect.

Method of administration and doses

Seretide Diskus is for inhalation use only.

Patients should be aware that Seretide Diskus must be used regularly, even when symptoms are absent.

Patients should be regularly reviewed to ensure that the dose selected for them remains optimally effective, which can only be changed by the doctor. The dose of the drug should be adjusted to the minimum effective dose that provides control of the symptoms of the disease. If such effective control is achieved against the background of the minimum effective dose of the drug when used twice a day, the next step may be to transfer the patient to the use of a single inhaled corticosteroid. As an alternative, for the treatment of patients who require the use of long-acting b 2 -agonists, the dose of Seretide Diskus can be reduced to 1 dose per day if, in the opinion of the doctor, adequate control of the symptoms of the disease is maintained. If the patient has a history of nocturnal asthma attacks, this single dose should be used at bedtime, if the history of symptoms mainly occurs during the day, the dose is used in the morning.

The amount of fluticasone propionate in the selected Seretide Diskus formulation should be appropriate for the severity of the disease. If the patient requires higher than recommended doses, appropriate doses of β2-agonists and/or corticosteroids should be administered.

Recommended doses.

Asthma

Adults and children aged 12 years and over:

one inhalation (50 mcg salmeterol/100 mcg fluticasone propionate) twice daily;

or one inhalation (50 mcg salmeterol/250 mcg fluticasone propionate) twice daily;

or one inhalation (50 mcg salmeterol/500 mcg fluticasone propionate) twice daily.

For the treatment of adults and adolescents with moderate persistent asthma (daily symptoms, daily use of quick-relief medication and moderate to severe airflow limitation), Seretide Diskus can be used as initial maintenance therapy when rapid control of symptoms is required. In such cases, the recommended starting dose is 1 inhalation of 50 micrograms salmeterol and 100 micrograms fluticasone propionate twice daily. Once asthma symptoms are controlled, therapy should be reviewed and a decision should be made whether to switch the patient to inhaled corticosteroid therapy alone. As the patient's treatment is reviewed, regular assessments of functional status should be made.

In the absence of one or two severity criteria, no clear advantage of Seretide Diskus over inhaled fluticasone propionate alone as initial maintenance therapy has been demonstrated. In general, inhaled corticosteroids remain the first-line treatment for most patients. Seretide Diskus is not indicated for the initial treatment of mild asthma. Seretide Diskus 50 mcg/100 mcg is not appropriate for the treatment of adults and children with severe asthma; for the treatment of patients with severe asthma, it is recommended that an appropriate dose of inhaled corticosteroid is first established before using any fixed combination.

Children aged 4 to 12 years: one inhalation (50 mcg salmeterol/100 mcg fluticasone propionate) twice daily.

The maximum daily dose of fluticasone propionate in Seretide Diskus for the treatment of children is 100 mcg twice a day.

There are no data on the use of Seretide Diskus in children under 4 years of age, therefore its use is not recommended.

Chronic obstructive pulmonary disease

Adults:

one inhalation (50 mcg salmeterol/500 mcg fluticasone propionate) twice daily.

Certain patient groups

There is no need to adjust the dose for elderly patients and patients with kidney or liver disease.

Instructions for using the inhaler

The diskus is designed to release the powder and then inhale it into the lungs.

The rules for using the Diskus inhaler are given below.

How to use the DISCUS inhaler

Inhaler position CLOSED

When you take your DISCUS inhaler out of the box, it should be closed.

Inhaler position OPEN

Your new DISCUS inhaler contains 60 doses of the medicine. An indicator shows you how many doses are left.

This DISCUS inhaler contains 60 individually packaged doses of your medication in powder form. This means that each dose is precisely measured and hygienically protected. There is no need for special care of the inhaler or refilling doses.

The dose indicator on the top of the DISCUS inhaler shows you how many doses of medicine are left. The numbers 5 to 0 appear in red to alert you that you only have a few doses left.

The DISCUS inhaler is easy to use. When you need to take a dose of the drug, you need to perform the following four manipulations, which are shown in the pictures below.

1. Open the inhaler.

2. Move the lever.

3. Inhale.

4. Close.

5. Rinse your mouth with water and spit it out.

When you press the lever on the DISCUS inhaler, a small hole in the mouthpiece opens and a dose is released, ready for you to inhale. When you close the DISCUS inhaler, the lever automatically returns to its original position and the inhaler is ready to prepare the next dose if needed. The case protects your DISCUS inhaler when it is not in use.

CLEANING

To clean, wipe the mouthpiece of the DISCUS inhaler with a dry cloth.

REMEMBER

Store your DISCUS inhaler in a dry place.

Keep it closed when not in use.

Never exhale into your DISCUS inhaler.

Only press the lever when you are ready to take a dose.

Never exceed the prescribed dose.

Children.

There are no data on the use of Seretide Diskus in children under 4 years of age, therefore the use of the drug in this age group is not recommended.

Overdose

There is no information on overdose with Seretide Diskus from clinical trials, however, overdose data for both active substances are provided below.

Signs and symptoms to be expected in case of overdose with salmeterol are those typical of β2-adrenergic stimulation: dizziness, tremor, headache, tachycardia, increased systolic blood pressure. If Seretide Diskus treatment has to be discontinued due to overdose of the β2-agonist contained in the product, appropriate steroid replacement therapy should be prescribed. Hypokalaemia may also occur, so potassium replacement therapy should be considered.

Acute overdose

Inhalation of fluticasone propionate in doses exceeding those recommended may cause temporary suppression of adrenal function. This does not require immediate action, as adrenal function recovers within a few days, which can be verified by measuring plasma cortisol.

Chronic overdose

There is a risk of adrenal suppression when using higher than approved doses of Seretide Diskus for a long time.

Very rare cases of acute adrenal crisis have been reported, mainly in children, who have been treated with doses higher than recommended for prolonged periods (several months or years). Hypoglycaemia associated with confusion and convulsions has been reported. Situations that may potentially precipitate acute adrenal crisis include trauma, surgery, infection and any rapid reduction in the dose of inhaled fluticasone propionate.

Monitoring of adrenal reserve is recommended. In the event of an overdose of fluticasone propionate with Seretide Diskus, therapy can be continued at appropriate doses to control symptoms.

There is no specific treatment for overdose of salmeterol and fluticasone propionate; supportive therapy with monitoring of the patient's condition is necessary.

Side effects

Adverse reactions associated with the use of salmeterol/fluticasone propionate are listed below and classified by system organ class and frequency. The frequency is defined as: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000) and unknown (cannot be estimated from the available data). Information on the frequency of occurrence is obtained from the results of clinical trials. Information on cases recorded in the placebo group is not taken into account.

1 Recorded as “common” in the placebo group.

2 Reported as “very common” in the placebo group.

3 Were recorded over 3 years during the COPD study.

4 See section "Application features".

5 See section “Pharmacological properties”.

Description of some adverse reactions

Pharmacological side effects of β2-agonist treatment, such as tremor, subjective palpitations, and headache, have been reported, but these are usually transient and decrease with regular use.

As with other inhaled medications, paradoxical bronchospasm may occur after inhalation with a rapid increase in dry wheezing and shortness of breath. Paradoxical bronchospasm is treated with a fast-acting