Seretide evohaler

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SERETIDE EVOHALER

Composition:

Active substances: salmeterol (as salmeterol xinafoate), fluticasone propionate;

One dose of the product contains 25 mcg salmeterol (as salmeterol xinafoate) and 50 mcg, or 125 mcg, or 250 mcg fluticasone propionate;

Excipient: propellant HFA 134a.

Pharmaceutical form. Pressurized metered-dose inhalation suspension.

Main physicochemical properties: white or almost white suspension.

Pharmacotherapeutic group. Antiasthmatics. Adrenergic agents for inhalation use. Adrenergic agents in combination with corticosteroids or other agents, excluding anticholinergics. Salmeterol and fluticasone. ATC code R03AK06.

Pharmacological Properties

Pharmacodynamics

Seretide Easi-Breathe contains salmeterol and fluticasone propionate, which have different mechanisms of action.

Salmeterol

Salmeter polic is a selective long-acting (12 hours) β2-adrenergic receptor agonist with a long side chain that binds to the external domain of the receptor.

Salmeterol provides longer-lasting bronchodilation (not less than 12 hours) than recommended doses of traditional short-acting β2-adrenergic agonists.

Fluticasone propionate

When administered by inhalation at recommended doses, fluticasone propionate exerts a pronounced glucocorticoid anti-inflammatory effect in the lungs, leading to a reduction in clinical symptoms and frequency of asthma exacerbations, without the adverse reactions observed with systemic corticosteroid administration.

Pharmacokinetics

When salmeterol and fluticasone propionate are used in combination via inhalation, the pharmacokinetics of each component remain the same as when each component is administered separately. Therefore, their pharmacokinetic characteristics are described individually.

Salmeterol

Salmeterol acts locally in lung tissue; therefore, its plasma concentration does not correlate with therapeutic effect. Furthermore, pharmacokinetic data on salmeterol are limited due to technical difficulties in measuring very low plasma concentrations of the drug (approximately 200 picograms/mL or less) following inhaled 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. Lower systemic exposure levels are observed in patients with asthma following inhaled administration of fluticasone propionate. Systemic absorption occurs primarily in the lungs, initially rapidly and then more slowly. A portion of the inhaled dose may be swallowed, but its systemic effect is minimal due to the low water solubility of fluticasone propionate and extensive first-pass metabolism in the liver. The bioavailability of fluticasone propionate following absorption from the gastrointestinal tract is less than 1%. A linear increase in systemic exposure to fluticasone propionate is observed with increasing inhaled doses. Distribution of fluticasone propionate is characterized by high plasma clearance (1150 mL/min), a large volume of distribution (approximately 300 L), and an elimination half-life of approximately 8 hours. Plasma protein binding is relatively high (91%). Fluticasone propionate is rapidly eliminated from systemic circulation, primarily via metabolism by the CYP3A4 enzyme of the cytochrome P450 system into an inactive carboxylic acid metabolite. Other unidentified metabolites are excreted in feces. Renal clearance of fluticasone propionate is negligible, with less than 5% of the dose excreted in urine, primarily as metabolites. The majority of the dose is excreted in feces as metabolites and unchanged drug.

Clinical characteristics.

Indications.

Regular treatment of bronchial asthma in patients requiring combination therapy with a long-acting β2-agonist and an inhaled corticosteroid:

• patients with inadequate control of bronchial asthma despite treatment with inhaled corticosteroids and short-acting β2-agonists as needed, or
• patients with adequate control of bronchial asthma on treatment with inhaled corticosteroids and long-acting β2-agonists administered via separate inhalers.

Contraindications.

Hypersensitivity to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Beta-adrenergic blockers may reduce or abolish the effect of salmeterol. The use of non-selective and selective beta-blockers should be avoided in patients with asthma, except when there are compelling medical reasons. Administration of β2-agonists may cause potentially dangerous hypokalaemia. The medicinal product should be prescribed with particular caution to patients with acute severe asthma, as concomitant use of xanthine derivatives, steroids, and diuretics may potentiate adverse reactions.

Concomitant administration with medicinal products containing other β-adrenergic agents may have a potential additive effect.

Fluticasone propionate.

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

Data from drug interaction studies involving healthy volunteers using intranasal fluticasone propionate show that ritonavir (a strong inhibitor of cytochrome CYP3A4), at a dose of 100 mg twice daily, increases plasma concentrations of fluticasone propionate by several hundred-fold, leading to a significant reduction in serum cortisol levels. Information regarding inhaled fluticasone propionate is lacking, but a substantial increase in serum levels of fluticasone propionate is expected. Cases of Cushing's syndrome and adrenal suppression have been reported. Concomitant use should be avoided, except when the therapeutic benefit outweighs the potential risk of systemic glucocorticoid adverse effects.

In a small interaction study with the less potent CYP3A inhibitor ketoconazole involving healthy volunteers, exposure to fluticasone propionate after one inhalation increased by 150%, resulting in a greater reduction in plasma cortisol levels compared to fluticasone propionate administered alone. Concomitant use with other strong CYP3A inhibitors (e.g., itraconazole, cobicistat-containing products) and moderate CYP3A inhibitors (e.g., 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 risk of developing systemic corticosteroid-related adverse effects. In such cases, patients should be monitored for the development of systemic adverse effects.

Salmetrol.

Strong CYP3A4 inhibitors

Concomitant 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 exposure to salmeterol (1.4-fold increase in maximum concentration (Cmax) and 15-fold increase in area under the concentration-time curve (AUC)). This may lead to an increased frequency of other systemic reactions to salmeterol (e.g., QT interval prolongation and palpitations) compared to administration of salmeterol or ketoconazole alone (see section "Special precautions for use").

No clinically significant effects on blood pressure, heart rate, blood glucose levels, or serum potassium levels were observed. Concomitant administration with ketoconazole did not increase the elimination half-life of salmeterol or lead to accumulation of salmeterol with repeated dosing.

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

Moderate CYP3A4 inhibitors

Concomitant administration of erythromycin (500 mg orally three times daily) and salmeterol (50 mcg inhaled twice daily) in 15 healthy volunteers for 6 days resulted in a small and statistically non-significant increase in plasma exposure to salmeterol (1.4-fold increase in Cmax and 1.2-fold increase in AUC). Concomitant use with erythromycin was not associated with any serious adverse reactions.

Special precautions for use.

Seretide Evohaler is not a medication for relieving acute symptoms requiring the use of fast- and short-acting bronchodilators (e.g., salbutamol). Patients should be advised to always carry a reliever medication for such symptoms.

Seretide Evohaler should not be initiated during an exacerbation of disease, or in cases of significant or acute worsening of the patient's condition and disease progression.

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

An increased need for short-acting bronchodilators to relieve symptoms of bronchial asthma, or a reduced response to such medications, indicates worsening asthma control and the need for medical consultation. Rapid and progressive deterioration in asthma control is potentially life-threatening and requires immediate medical attention. Consideration should be given to increasing corticosteroid dosage. Patients should also be evaluated by a physician if the prescribed dose of Seretide Evohaler fails to provide adequate asthma symptom control.

When asthma symptoms are controlled, the dose of Seretide Evohaler should be gradually reduced. Regular monitoring of the patient's condition is essential during dose reduction. The lowest effective dose of Seretide Evohaler should be used (see section "Dosage and administration").

Treatment should not be discontinued abruptly, as this may increase the risk of disease exacerbation. Dose reduction should be performed gradually under medical supervision.

As with any other inhaled corticosteroid-containing medication, Seretide Evohaler should be prescribed 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 increased systolic blood pressure and heart rate may occur with all sympathomimetic agents, especially at high doses. Therefore, the medication should be used cautiously in patients with cardiovascular disorders.

Rarely, high therapeutic doses of Seretide Evohaler may cause cardiac arrhythmias, such as supraventricular tachycardia, extrasystoles, or atrial fibrillation, as well as mild transient reduction in serum potassium levels. Therefore, the medication should be used with caution in patients with severe cardiovascular disease, cardiac arrhythmias, hyperthyroidism, diabetes mellitus, uncorrected hypokalemia, or those predisposed to low serum potassium levels.

There have been very rare reports of increased blood glucose levels (see section "Adverse reactions"). This should be considered when prescribing the medication to patients with a history of diabetes mellitus.

As with other inhaled medications, paradoxical bronchospasm with sudden worsening of breathlessness after inhalation may occur. Immediate treatment with a fast-acting inhaled short-acting bronchodilator is required. Seretide Evohaler should be discontinued immediately, the patient should be evaluated, and alternative therapy initiated if necessary.

Pharmacological adverse effects associated with β2-agonists such as tremor, palpitations, and headache have been reported, but these are transient and tend to diminish with regular therapy (see section "Adverse reactions").

Systemic effects may occur with inhaled corticosteroids, particularly when used at high doses over prolonged periods. These effects are much less likely than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, decreased bone mineralization, cataracts, and glaucoma, and less frequently, a range of physiological and behavioral reactions including psychomotor hyperactivity, sleep disturbances, anxiety, depression, and aggression (particularly in children). Therefore, it is important to monitor the patient's condition and reduce the inhaled corticosteroid dose to the lowest effective dose sufficient to control symptoms of bronchial asthma.

Prolonged therapy 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 ranging from 500 mcg to 1000 mcg. Situations that may potentially trigger acute adrenal crisis include trauma, surgery, infections, or any rapid dose reduction. Symptoms are often nonspecific and may include anorexia, abdominal pain, weight loss, fatigue, headache, nausea, vomiting, hypotension, decreased level of consciousness, hypoglycemia, and seizures. During periods of stress or surgery, consideration should be given to the need for additional systemic corticosteroid therapy due to possible adrenal impairment.

Systemic absorption of salmeterol and fluticasone propionate occurs primarily via the lungs. Since using a spacer with the inhaler may increase drug delivery to the lungs, the risk of systemic adverse reactions may be increased. Pharmacokinetic studies of single doses have shown that systemic exposure to salmeterol and fluticasone propionate may be doubled when using the AeroChamber Plus spacer compared to the VoluMate spacer.

Inhaled fluticasone propionate minimizes the need for oral corticosteroids, but patients transitioning from oral corticosteroids remain at risk of adrenal reserve impairment for some time. Such patients should be managed with particular care and regular monitoring of adrenal cortex function. Patients who have previously received high-dose corticosteroids as emergency treatment also carry this risk. Residual adrenal insufficiency should always be considered in emergency situations or stressful conditions, and the need for corticosteroid therapy should be evaluated (see section "Overdose"). Special consultation may be required before certain procedures to assess the degree of adrenal insufficiency.

Due to the potential for adrenal suppression, patients should be switched from oral corticosteroid therapy to Seretide Evohaler with particular caution.

When initiating inhaled fluticasone propionate, discontinuation of systemic therapy should be gradual. Patients should be advised to carry a steroid alert card indicating the potential need for additional therapy during stressful situations.

Ritonavir may significantly increase plasma concentrations of fluticasone propionate. Therefore, concomitant use of these medications should be avoided, except when the expected benefit to the patient outweighs the potential risk of systemic corticosteroid adverse reactions. The risk of systemic adverse reactions is also increased when fluticasone propionate is used concomitantly with other potent inhibitors of cytochrome CYP3A.

In a three-year clinical study in patients with chronic obstructive pulmonary disease (COPD), an increased incidence of lower respiratory tract infections (mainly pneumonia and bronchitis) was observed with salmeterol and fluticasone propionate delivered via the Diskus device compared to placebo. In this three-year study involving COPD patients, older patients, those with low body mass index (<25 kg/m²), and those with very severe disease (FEV1 <30% of predicted) had a higher risk of pneumonia regardless of treatment. Physicians should consider the possibility of pneumonia or other lower respiratory tract infections in COPD patients, as clinical symptoms of pneumonia and COPD exacerbation often overlap. If pneumonia develops in a patient with severe COPD, the continued use of Seretide Evohaler should be re-evaluated. The safety and efficacy of Seretide Evohaler in patients with COPD have not been established; therefore, Seretide Evohaler is not indicated for use in patients with COPD.

Concomitant use with systemic ketoconazole significantly increases systemic exposure to salmeterol, potentially leading to increased frequency of systemic adverse reactions (e.g., QT interval prolongation and palpitations). Therefore, concomitant use with ketoconazole and other strong CYP3A inhibitors should be avoided, except when the expected benefit outweighs the potential risk of systemic adverse reactions to salmeterol (see section "Interaction with other medicinal products and other forms of interaction").

Visual disturbances

Visual disturbances may occur with both systemic and local use of corticosteroids. If a patient experiences symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist to evaluate possible causes, including cataracts, glaucoma, or rare conditions such as central serous chorioretinopathy, which has been reported after systemic and topical corticosteroid use.

Children

Children and adolescents under 16 years of age receiving high doses of fluticasone propionate (usually ≥1000 mcg/day) are at particular risk of systemic adverse reactions. Systemic effects are more likely with prolonged high-dose therapy. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, acute adrenal crisis, growth retardation in children and adolescents, and less frequently, psychiatric and behavioral disorders including psychomotor hyperactivity, sleep disturbances, anxiety, depression, or aggression.

Regular monitoring of growth in children receiving long-term inhaled corticosteroid therapy is recommended. The dose of inhaled corticosteroid should be reduced to the lowest effective dose sufficient to control asthma symptoms.

Use during pregnancy or breastfeeding.

Pregnancy

Extensive data from over 1000 cases of use of Seretide Evohaler in pregnant women have shown no evidence of embryotoxic or fetotoxic effects.

Results of a retrospective epidemiological study showed no increased risk of major congenital malformations after exposure to fluticasone propionate during the first trimester of pregnancy compared to other inhaled corticosteroids.

Reproductive toxicity has been observed in animal studies with β2-adrenergic agonists and glucocorticosteroids.

Seretide Evohaler should be used during pregnancy only if the expected benefit to the mother clearly outweighs the potential risk to the fetus. The lowest effective dose of fluticasone propionate necessary to adequately control bronchial asthma symptoms should be prescribed for pregnant women.

Breastfeeding

It is unknown whether salmeterol, fluticasone propionate, or their metabolites are excreted in human breast milk.

Animal studies in rats have shown that salmeterol, fluticasone propionate, and their metabolites are excreted in milk. Therefore, a risk to the infant cannot be excluded during breastfeeding while the mother is receiving this medication. The decision whether to discontinue breastfeeding or to discontinue therapy with Seretide Evohaler should be based on the benefits of breastfeeding to the child and the expected benefits of treatment to the mother.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

Seretide Evohaler has no effect or a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

Seretide Evohaler is intended for inhalation use only.

Patients should be aware that Seretide Evohaler must be used regularly, even during periods free of bronchial asthma attacks.

Patients should undergo regular medical evaluations to ensure the prescribed dose remains optimally effective. Dose adjustments may only be made by a physician. The dose should be titrated to the lowest effective dose that maintains control of disease symptoms. If adequate symptom control is achieved with the lowest effective dose administered twice daily, the next step may be transitioning the patient to a single inhaled corticosteroid. Alternatively, for patients requiring long-acting β2-agonists, the dose of Seretide Evohaler may be reduced to once daily if, in the physician’s opinion, this adequately maintains symptom control. If the patient has a history of nocturnal asthma attacks, the single daily dose should be taken at bedtime. If attacks occur predominantly during the day, the dose should be taken in the morning.

The amount of fluticasone propionate in the chosen formulation of Seretide Evohaler should correspond to the severity of the disease.
Note: Seretide Evohaler 25 mcg/50 mcg is not appropriate for the treatment of adults or children with severe bronchial asthma. If an individual patient requires doses outside the recommended regimen, appropriate doses of β2-agonist and/or corticosteroid should be prescribed separately.

Recommended Dosages

Adults and adolescents aged 12 years and older:

• 2 inhalations of 25 mcg salmeterol/50 mcg fluticasone propionate twice daily,
• or 2 inhalations of 25 mcg salmeterol/125 mcg fluticasone propionate twice daily,
• or 2 inhalations of 25 mcg salmeterol/250 mcg fluticasone propionate twice daily.

For the treatment of adults and adolescents with moderate persistent bronchial asthma (daily symptoms, daily use of reliever medication, and moderate to severe airflow limitation), Seretide Evohaler may be used as initial maintenance therapy when rapid symptom control is required. In such cases, the recommended starting dose is: 2 inhalations of 25 mcg salmeterol/50 mcg fluticasone propionate twice daily. After achieving asthma symptom control, a step-down in therapy to inhaled corticosteroid monotherapy should be considered. When stepping down therapy, regular patient monitoring is essential.

If one or both severity criteria are absent, no clear advantage of using Seretide Evohaler over inhaled fluticasone propionate alone as initial maintenance therapy has been demonstrated. In general, inhaled corticosteroids remain first-line therapy for most patients. Seretide Evohaler should not be prescribed for initial treatment of mild bronchial asthma. Seretide Evohaler 25 mcg/50 mcg is not suitable for treating adults or children with severe bronchial asthma. For patients with severe asthma, it is recommended to first establish an appropriate dose of inhaled corticosteroid before initiating any fixed-dose combination.

Children

Children aged 4–12 years:

• 2 inhalations of 25 mcg salmeterol/50 mcg fluticasone propionate twice daily.

The maximum daily dose of fluticasone propionate in Seretide Evohaler is 100 mcg twice daily.

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

Special Patient Groups

Dose adjustment is not required for elderly patients or patients with renal impairment. Data on the use of Seretide Evohaler in patients with hepatic impairment are lacking.

Instructions for Inhaler Use

Patients must be instructed on the proper use of the inhaler. Inhalation should be performed while standing or sitting. This inhaler is specifically designed for use in an upright position.

Checking the Inhaler

Before first use or after a break in use exceeding 1 week, remove the mouthpiece cap by gently pressing the sides, shake the inhaler well, and release two sprays into the air to ensure proper functioning.

Using the Inhaler

1. Remove the mouthpiece cap by gently pressing the sides.
2. Ensure the inside and outside of the inhaler, including the mouthpiece, are free of foreign objects.
3. Shake the inhaler thoroughly to remove any foreign material and to ensure uniform mixing of the contents.
4. Hold the inhaler vertically in the hand between the index and other fingers, with the thumb placed on the body of the inhaler below the mouthpiece.
5. Breathe out fully, then place the mouthpiece in the mouth between the teeth and seal lips around it without biting.
6. While inhaling slowly and deeply through the mouth, press down on the top of the inhaler to release a spray. Continue inhaling slowly and deeply. One press equals one dose.
7. Hold the breath, remove the inhaler from the mouth, and remove the finger from the top of the inhaler. Continue holding the breath as long as possible.
8. If additional sprays are needed, wait approximately 30 seconds, keeping the inhaler upright. Then repeat steps 3–7.
9. Rinse the mouth with water and spit it out.
10. Replace the mouthpiece cap by pressing until it clicks into place.

IMPORTANT

Perform steps 5, 6, and 7 without rushing. Inhalation before actuation should be as slow as possible. The first few times, practice in front of a mirror. If a "mist" appears around the top of the inhaler or at the corners of the mouth, restart the procedure from step 3.

Immediately after use, close the mouthpiece with the cap by gently pressing until a click is heard. Do not apply excessive force.

Rinsing the mouth, spitting out water, and/or tooth brushing after each use of the medication minimizes the risk of oropharyngeal candidiasis and hoarseness.

As with other inhaled medications, therapeutic efficacy may be reduced if the canister is cold.

The canister contains pressurized liquid. Do not expose to temperatures above 50°C or direct sunlight. Do not disassemble, puncture, or incinerate the canister, even when empty.

Disposal of unused medication or used container must comply with local regulations.

If the physician provides different instructions for inhaler use, follow those and seek advice if any difficulties arise.

Children

An adult may need to assist children with inhalation. Ask the child to exhale and administer the spray immediately after inhalation begins. It is recommended to practice the technique together. Older children or weakened adults may hold the inhaler with both hands. Place both index fingers on the top of the inhaler and both thumbs on the base below the mouthpiece.

Cleaning

The inhaler should be cleaned at least once a week.

1. Remove the mouthpiece cap.
2. Do not remove the metal canister from the plastic holder.
3. Wipe the inside and outside of the mouthpiece cap and the plastic holder with a dry cloth.
4. Replace the mouthpiece cap until it clicks into place, without applying excessive force.

DO NOT PUT THE METAL CANISTER IN WATER.

Children

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

Overdose

Clinical trial data do not report cases of overdose with Seretide Evohaler; however, information on overdose with each of the active ingredients is provided below.

Signs and symptoms expected with salmeterol overdose are typical of excessive β2-agonist stimulation, including dizziness, tremor, headache, tachycardia, and increased systolic blood pressure. If treatment with Seretide Evohaler must be discontinued due to overdose of the β2-agonist component, appropriate replacement corticosteroid therapy should be initiated. Hypokalemia may also occur; therefore, serum potassium levels should be monitored and potassium replacement considered.

Acute Overdose

Inhalation of fluticasone propionate in doses exceeding the recommended amount may cause transient suppression of adrenal function. This does not require emergency intervention, as adrenal function recovers within a few days, which can be confirmed by measuring plasma cortisol levels.

Chronic Overdose

There is a risk of adrenal suppression with prolonged use of Seretide Evohaler at doses higher than approved.

Very rare cases of acute adrenal crisis have been reported, primarily in children who received higher-than-recommended doses over prolonged periods (several months or years). Hypoglycemia associated with confusion and seizures has been observed. Factors potentially triggering acute adrenal crisis include trauma, surgery, infection, and any rapid reduction in the dose of inhaled fluticasone propionate.

Monitoring of adrenal reserve function is recommended. In cases of fluticasone propionate overdose during Seretide Evohaler use, therapy may be continued at appropriate doses that maintain symptom control.

There is no specific antidote for salmeterol or fluticasone propionate overdose; supportive treatment with close patient monitoring is required.

Adverse reactions.

Since Seretide Evohaler contains salmeterol and fluticasone propionate, adverse reactions typical of each component in terms of type and severity can be expected. Additional adverse reactions due to the concomitant use of both components have not been observed.

Adverse reactions associated with the use of salmeterol/fluticasone propionate are listed below (table) and classified by organ systems and frequency of occurrence. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and not known (cannot be estimated from the available data). Frequency data are derived from clinical trial results. Information regarding events observed in the placebo group has not been included.

Organs and organ systems	Adverse reaction	Frequency
Infections and infestations	Oral and pharyngeal mucosal candidiasis Pneumonia Bronchitis Esophageal candidiasis	Common Common1,3 Common1,3 Uncommon
Immune system disorders	Hypersensitivity reactions: skin hypersensitivity reactions, angioedema (mainly of the face and oropharynx), respiratory symptoms (dyspnea), respiratory symptoms (bronchospasm), anaphylactic reactions, including anaphylactic shock	Uncommon Uncommon Uncommon Uncommon Uncommon
Endocrine system disorders	Cushing's syndrome, Cushingoid symptoms, adrenal suppression, growth retardation in children and adolescents, decreased bone mineralization	Uncommon4
Metabolism and nutrition disorders	Hypokalemia Hyperglycemia	Common3,4 Uncommon
Psychiatric disorders	Restlessness Sleep disturbances Behavioral changes including psychomotor hyperactivity and irritability (mainly in children) Depression, aggression (mainly in children)	Uncommon Uncommon Uncommon Unknown
Nervous system disorders	Headache Tremor	Very common1 Uncommon
Eye disorders	Cataract Glaucoma Blurred vision	Uncommon Uncommon4 Unknown4
Cardiac disorders	Pounding heartbeat Tachycardia Cardiac arrhythmia (including supraventricular tachycardia and extrasystoles) Atrial fibrillation Angina pectoris	Uncommon Uncommon Uncommon Uncommon Uncommon
Respiratory system disorders	Nasopharyngitis Throat irritation Hoarseness/dysphonia Sinusitis Paradoxical bronchospasm	Very common2,3 Common Common Common1,3 Uncommon4
Skin and subcutaneous tissue disorders	Contusions	Common1,3
Musculoskeletal and connective tissue disorders	Muscle spasms Traumatic fractures Arthralgia Myalgia	Common Common Common Common

1Reported as "common" in the placebo group.

2Reported as "very common" in the placebo group.

3Observed over 3 years during the COPD study.

4See section "Special precautions".

Description of some adverse reactions

Pharmacological adverse reactions associated with β2-agonists such as tremor, palpitations, and headache have been reported, but these are usually transient and tend to diminish with regular use.

As with other inhaled medications, paradoxical bronchospasm with rapid increase in wheezing and shortness of breath may occur after inhalation. Paradoxical bronchospasm is responsive to fast-acting bronchodilators, and treatment should be initiated immediately. In such cases, use of Seretide Evohaler should be discontinued immediately, the patient should be examined, and alternative therapy should be considered if necessary.

Due to the presence of fluticasone propionate in Seretide Evohaler, some patients may experience hoarseness, oropharyngeal candidiasis, and rarely esophageal candidiasis.

The incidence of hoarseness and oropharyngeal candidiasis can be reduced by rinsing the mouth with water and/or brushing teeth after inhalation. Symptomatic treatment of oropharyngeal candidiasis may be carried out with topical antifungal agents without discontinuing Seretide Evohaler.

Paediatric population

In children and adolescents, systemic effects including Cushing's syndrome, Cushingoid features, adrenal suppression, and growth retardation may occur. Children may also experience anxiety, sleep disturbances, and behavioural changes such as hyperactivity and irritability.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions following marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients can report suspected adverse reactions to GlaxoSmithKline Pharmaceuticals Ukraine LLC via the 24-hour hotline (044) 585-51-85 or by email at [email protected].

Shelf life. 2 years.

Storage conditions.

Store below 30°C. Do not freeze.

Protect from direct sunlight.

Keep out of the reach of children.

Packaging.

One 120-dose aerosol aluminium alloy canister with an internal coating and metering valve. Each canister is equipped with a plastic spray actuator and a dust cap. The canister is placed in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Glaxo Wellcome Production, France.

Manufacturer's name and address.

Zone Industrielle №2, 23, rue Lavoisier, 27000 Evreux, France.