Seroflo-125

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CЕROFLO-50, CЕROFLO-125, CЕROFLO-250 (SEROFLO-50, SEROFLO-125, SEROFLO-250)

Composition:

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

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

Excipient: tetrafluoroethane (HFA-134a).

Pharmaceutical form. Pressurized metered-dose inhalation aerosol.

Main physicochemical properties: white powder.

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

Pharmacological properties.

Pharmacodynamics.

The medicinal product contains salmeterol and fluticasone propionate, which have different mechanisms of action.

Salmetrol

Salmetrol is a selective long-acting (12 hours) β2-adrenoceptor agonist with a long side chain attached to the external domain of the receptor.

Salmetrol provides more prolonged bronchodilation (not less than 12 hours) than the recommended doses of traditional short-acting β2-adrenoceptor 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 exacerbations of bronchial asthma without causing adverse reactions observed with systemic administration of corticosteroids.

Pharmacokinetics.

When salmeterol and fluticasone propionate are used in combination by inhalation, the pharmacokinetics of each component remains the same as when these components are used separately; therefore, their pharmacokinetics are described separately.

Salmetrol

Salmetrol acts locally in lung tissue, and therefore its plasma concentration does not correlate with therapeutic effect. Furthermore, pharmacokinetic data for salmetrol are limited due to technical difficulties in measuring very low plasma concentrations of the drug (approximately 200 pg/mL and lower) following inhaled administration at therapeutic doses.

Fluticasone propionate

The absolute bioavailability of fluticasone propionate after inhaled administration in healthy volunteers is approximately 5–11% of the nominal dose, depending on the inhalation device used. Lower levels of systemic exposure are observed in patients with bronchial asthma following inhaled administration of fluticasone propionate. Systemic absorption occurs primarily in the lungs, initially rapidly and then slowing down. A portion of the inhaled dose may be swallowed, but its systemic effect is minimal due to the poor 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 plasma concentration of fluticasone propionate is observed with increasing inhaled dose. The distribution of fluticasone propionate is characterized by high plasma clearance (1150 mL/min), a large volume of distribution (approximately 300 L), and a terminal half-life of approximately 8 hours. The extent of plasma protein binding is relatively high (91%). Fluticasone propionate is rapidly eliminated from systemic circulation, primarily by metabolism to an inactive carboxylic acid metabolite via the CYP3A4 enzyme of the cytochrome P450 system. Other unidentified metabolites are excreted in feces. Renal clearance of fluticasone propionate is very low; less than 5% of the dose is excreted in urine, mainly as metabolite. 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:

long-acting β2-adrenergic agonists and inhaled corticosteroids:

• when poor control of bronchial asthma persists despite therapy with inhaled corticosteroids and short-acting β2-agonists as needed;
• when adequate control of bronchial asthma is achieved with therapy using 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.

β-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 hypokalemia. The medicinal product should be prescribed with particular caution in patients with acute severe asthma, as concomitant use of xanthine derivatives, steroids, and diuretics may potentiate adverse reactions.

Concomitant use with medicinal products containing other β-adrenergic agents may result in additive effects.

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 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 studies in healthy volunteers using intranasal fluticasone propionate have shown that ritonavir (a strong inhibitor of cytochrome CYP3A4) can significantly increase plasma concentrations of fluticasone propionate, leading to a substantial reduction in serum cortisol levels. Although such data for inhaled fluticasone propionate are limited, a marked increase in serum fluticasone propionate levels is expected. Cases of Cushing's syndrome and adrenal suppression have been reported. Concomitant use should be avoided unless the potential benefit outweighs the increased risk of systemic glucocorticoid side effects.

In a small study in healthy volunteers, co-administration with ketoconazole (a moderately potent CYP3A inhibitor) increased exposure to fluticasone propionate by 150% after one inhalation, resulting in a greater reduction in plasma cortisol levels compared to fluticasone propionate alone. Concomitant use with other strong CYP3A inhibitors (e.g., itraconazole, cobicistat-containing products) or 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.

Salmetarol

Strong CYP3A4 inhibitors

Concomitant administration of ketoconazole (400 mg orally once daily) and salmeterol (50 mcg inhaled twice daily) for 7 days in 15 healthy volunteers 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 incidence of other systemic effects of salmeterol treatment (e.g., QT interval prolongation and tachycardia) compared to administration of salmeterol or ketoconazole alone (see section "Special precautions").

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

Concomitant use with ketoconazole should be avoided unless the benefit outweighs the potential risk of systemic adverse reactions associated with salmeterol therapy. 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) for 6 days in 15 healthy volunteers 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 effects.

Special precautions for use.

This medicinal product is not a medication for the relief of acute symptoms requiring the use of fast-acting and short-acting bronchodilators (e.g., salbutamol). Patients should be advised to always have a reliever medication available.

Treatment with this medicinal product should not be initiated in patients during an exacerbation of the disease, particularly in cases of significant or acute worsening of the patient's condition and disease course.

Serious asthma-related adverse events and exacerbations may occur during treatment with this product. Patients should be advised to continue treatment but to seek medical advice if symptoms remain uncontrolled or worsen after initiation of therapy.

An increased use of short-acting bronchodilators to relieve symptoms of bronchial asthma 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 the dose of corticosteroids. The patient also requires medical evaluation if the prescribed dose of the medicinal product fails to provide adequate control of asthma symptoms.

When control of bronchial asthma symptoms has been achieved, the dose of the medicinal product should be gradually reduced. Regular monitoring of the patient is important during dose reduction. The lowest effective dose of the medicinal product should be used (see section "Dosage and administration").

Treatment with this medicinal product must not be abruptly discontinued due to the risk of disease exacerbation. The dose should be gradually reduced under medical supervision.

As with all inhaled corticosteroid-containing medicinal products, this product should be prescribed with caution in patients with active or latent pulmonary tuberculosis, fungal, viral, or other respiratory tract infections. 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 when high doses are used. Therefore, this medicinal product should be used with caution in patients with cardiovascular disorders.

Rarely, when used at high therapeutic doses, this product may cause cardiac rhythm disturbances, such as supraventricular tachycardia, extrasystoles, or atrial fibrillation, and mild transient reduction in serum potassium levels. Therefore, this product should be used with caution in patients with cardiovascular diseases, cardiac arrhythmias, diabetes mellitus, thyrotoxicosis, uncorrected hypokalemia, or patients predisposed to low serum potassium levels.

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

As with other inhaled medicinal products, paradoxical bronchospasm with immediate increase in dyspnea after inhalation may occur. Immediate treatment with a fast-acting inhaled short-acting bronchodilator is required. The product should be discontinued immediately, the patient evaluated, and alternative therapy initiated if necessary.

Adverse pharmacological effects associated with β2-agonist therapy such as tremor, palpitations, and headache have been reported, but these are transient and tend to diminish with regular use (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 (see section "Overdose"). Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, decreased bone mineralization, cataract, and glaucoma, as well as less frequently, a range of physiological and behavioral effects including psychomotor hyperactivity, sleep disturbances, anxiety, depression, and aggression (especially in children). Therefore, it is important to monitor the patient and reduce the inhaled corticosteroid dose to the lowest effective dose sufficient to control bronchial asthma symptoms.

Prolonged treatment of patients with high doses of inhaled corticosteroids may lead to suppression of adrenal function 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 daily. Situations that may potentially trigger acute adrenal crisis include trauma, surgery, infections, or any rapid dose reduction. Symptoms are usually 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 surgical procedures, consideration should be given to the need for additional systemic corticosteroids due to possible adrenal insufficiency.

Systemic absorption of salmeterol and fluticasone propionate occurs primarily via the lungs. Since the use of a spacer with the inhaler may increase drug delivery to the lungs, this should be considered, as it may increase the risk of systemic adverse effects. Single-dose pharmacokinetic studies have demonstrated that systemic exposure to salmeterol and fluticasone propionate may increase up to 2-fold when using the AeroChamber Plus spacer compared to the VoluMatic spacer.

Inhaled fluticasone propionate should minimize the need for oral steroid therapy, but patients transitioning from oral steroids may remain at risk of adrenal reserve impairment for some time. Therefore, 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. The possibility of residual insufficiency should always be considered in emergency situations or potential stress 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 transferred from oral corticosteroid therapy to treatment with this product with particular caution.

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

Concomitant use of ritonavir may significantly increase plasma concentrations of fluticasone propionate. Therefore, concomitant use of these medicinal products should be avoided, except when the anticipated benefit to the patient outweighs the potential risk of systemic corticosteroid adverse reactions. The risk of systemic adverse effects is also increased when fluticasone propionate is used concomitantly with other strong CYP3A inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

A three-year clinical study in patients with chronic obstructive pulmonary disease (COPD) showed an increased incidence of lower respiratory tract infections (mainly pneumonia and bronchitis) with the use of this product compared to placebo. In the three-year COPD study, older patients, patients with low body mass index (<25 kg/m²), and patients with very severe disease (FEV1 < 30% predicted) had a higher risk of pneumonia regardless of treatment received. Physicians should be vigilant for possible development of pneumonia or other lower respiratory tract infections in these patients, as clinical symptoms of pneumonia and COPD exacerbation often overlap. If pneumonia develops in a patient with severe COPD, the continued use of this product should be reconsidered. The safety and efficacy of this medicinal product in patients with COPD have not been established; therefore, this product should not be prescribed to patients with COPD.

Concomitant use with systemic ketoconazole significantly increases systemic exposure to salmeterol, potentially leading to increased systemic effects (e.g., QT interval prolongation and enhanced 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 effects from salmeterol treatment (see section "Interaction with other medicinal products and other forms of interaction").

Visual disturbances

Visual disturbances may occur with both systemic and topical corticosteroid use. If a patient develops symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist for evaluation of possible causes, including cataract, 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 effects. Systemic effects are generally associated with long-term, high-dose treatment. 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, agitation, 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 required to control asthma symptoms.

Use during pregnancy or breastfeeding.

Pregnancy

Extensive data on the use of this product in pregnant women (over 1000 cases) have shown no evidence of embryotoxic or fetotoxic effects on the fetus or newborn.

Results from a retrospective epidemiological study did not show an increased risk of major congenital malformations after exposure to fluticasone propionate during the first trimester of pregnancy compared to other inhaled corticosteroids.

Animal studies have shown reproductive toxicity after administration of β2-adrenergic agonists and glucocorticosteroids.

This medicinal product 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 control bronchial asthma symptoms adequately should be prescribed for pregnant women.

Breastfeeding

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

Animal studies in rats have shown that salmeterol and fluticasone propionate are excreted in female rat milk. Therefore, a risk to the infant from breastfeeding during maternal treatment with this medicinal product cannot be excluded. The decision whether to discontinue breastfeeding or discontinue/abstain from using the medicinal product should be based on the benefits of breastfeeding to the child and the benefits of therapy to the mother.

Fertility

There are no data on effects on human fertility. Studies in animals did not show effects of salmeterol or fluticasone propionate on fertility.

Ability to influence reaction rate while driving or operating machinery.

This medicinal product has no effect or a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

The medication is intended for inhalation use only.

Patients should understand that the medication must be used regularly, even during periods when there are no asthma attacks.

Patients should undergo regular medical examinations to ensure that the prescribed dose remains optimally effective. Dose adjustments may be made only by a physician. The dose should be titrated to the lowest effective dose that provides 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 an inhaled corticosteroid alone. As an alternative for patients requiring long-acting β₂-agonists, the dose of the medication may be reduced to once daily if, in the physician’s opinion, adequate symptom control is maintained. If the patient has a history of nocturnal asthma attacks, the single daily dose should be administered before bedtime; if symptoms occur during the day, the dose should be taken in the morning.

The amount of fluticasone propionate in the selected formulation should correspond to the severity of the disease. Note: Seroflo-50 is not suitable for the treatment of adults and children with severe asthma. It should be noted that fluticasone propionate is effective in doses equivalent to half the daily dose of other inhaled corticosteroids when used in the treatment of bronchial asthma. For example, 100 mcg of fluticasone propionate is approximately equivalent to 200 mcg of beclomethasone dipropionate (containing chlorofluorocarbons) or budesonide. If an individual patient requires doses outside the recommended regimen, appropriate doses of a β₂-agonist and/or corticosteroid should be prescribed.

Recommended Doses

Adults and children 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 rescue medication, and moderate to severe airflow limitation), the medication may be used as a starting maintenance therapy if 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 should be considered, transitioning to an inhaled corticosteroid alone. When stepping down therapy, regular patient monitoring is essential.

If one or both severity criteria are not clearly met, no clear advantage of using this medication over using inhaled fluticasone propionate alone as initial maintenance therapy has been demonstrated. In general, inhaled corticosteroids remain first-line therapy for most patients. The medication should not be used for initial treatment of mild asthma. Seroflo 25 mcg/50 mcg is not suitable for the treatment of adults and children with severe 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 the medication is 100 mcg twice daily.

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

Special Patient Groups

No dose adjustment is necessary for elderly patients or patients with renal impairment. Data on the use of the medication in patients with hepatic impairment are lacking.

Instructions for Inhaler Use

Patients should 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 the 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 2 sprays into the air to ensure proper functioning.

The inhaler should be shaken immediately before each spray.

After a break in use exceeding 1 week, remove the mouthpiece cap, shake the inhaler well, and release 2 sprays into the air.

Using the Inhaler

1. Remove the mouthpiece cap by gently pressing the sides.
2. Ensure that 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 between the thumb and other fingers, with the thumb placed on the body of the inhaler below the mouthpiece.
5. Breathe out fully, then place the mouthpiece between the teeth and seal the 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 dose of salmeterol. One press corresponds to 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 a click is heard.

IMPORTANT

Steps 5, 6, and 7 should be performed without rushing. Inhalation should be as slow as possible just before spraying. The first few times, practice in front of a mirror. If a "mist" appears around the top of the inhaler or at the sides 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 the water, and/or brushing teeth after each use of the medication minimizes the risk of oropharyngeal candidiasis and hoarseness.

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

The canister contains pressurized liquid. Do not heat above 50°C; protect from direct sunlight. Do not disassemble, puncture, or incinerate the canister, even after complete use.

Disposal of unused medication or used containers should be in accordance with local regulations.

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

Children

Adult supervision may be necessary when administering inhalations to children. 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.

Spacer

Children and patients with coordination difficulties may require the use of a spacer device. When selecting a spacer, follow the physician’s recommendations and the spacer’s instructions for use. Patients should use the same spacer consistently, as changing spacers may affect the dose delivered to the lungs. At the beginning of treatment with a spacer or when replacing a spacer, the lowest effective dose of the medication should be used.

Dose Indicator

The patient should obtain a new aerosol when the dose indicator shows "40" and the color changes from green to red. Use of the medication should be discontinued when the indicator shows "0". At "0", any remaining medication in the inhaler is insufficient to deliver a full dose.

Do not attempt to alter the numbers on the indicator or detach the indicator from the dispenser.

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 surfaces of the mouthpiece cap and the plastic holder with a dry cloth.
4. Replace the mouthpiece cap until a click is heard, without applying excessive force.

DO NOT IMMERSE THE METAL CANISTER IN WATER.

Children

The lack of sufficient clinical data on the use of the medication for treating children under 4 years of age does not permit its use in this age group.

Overdose

Clinical studies provide no information on cases of overdose; however, data on overdose with each of the active ingredients are 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 the medication must be discontinued due to overdose of the β₂-agonist component, appropriate corticosteroid replacement therapy should be initiated. Hypokalemia may also occur; therefore, serum potassium levels should be monitored, and potassium replacement therapy should be considered if necessary.

Acute Overdose

Inhalation of fluticasone propionate in doses exceeding the recommended amount may cause temporary 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 when higher-than-approved doses of the medication are used over a prolonged period.

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

Monitoring of adrenal reserve function is recommended. In cases of fluticasone propionate overdose, therapy may continue at appropriate doses that maintain symptom control.

There is no specific antidote for overdose with salmeterol and fluticasone propionate; supportive therapy with close monitoring of the patient’s condition is required.

Adverse reactions.

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

Adverse effects associated with the use of salmeterol/fluticasone propionate are listed below and classified by organ systems and frequency of occurrence. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000, < 1/1000), and not known (cannot be estimated from available data).

Organs and systems	Adverse reaction	Frequency
Infections and infestations	Oral and pharyngeal mucosal candidiasis Esophageal candidiasis Pneumonia Bronchitis	Common Rare Common1,3 Common1,3
Immune system disorders	Hypersensitivity reactions: skin hypersensitivity reactions, rash angioedema (mainly face and oropharynx) respiratory symptoms (dyspnea) respiratory symptoms (bronchospasm) anaphylactic reactions, including anaphylactic shock	Uncommon Rare Uncommon Rare Rare
Endocrine system disorders	Cushing's syndrome, cushingoid symptoms, adrenal suppression, growth retardation in children and adolescents, decreased bone mineralization	Rare4
Metabolism and nutrition disorders	Hypokalemia Hyperglycemia	Common3,4 Uncommon
Gastrointestinal disorders	Dyspepsia, nausea	Very rare
Psychiatric disorders	Nervousness Insomnia Restlessness, sleep disturbances Behavioral changes including psychomotor hyperactivity and irritability (mainly in children) Depression, aggression (mainly in children)	Uncommon Rare Uncommon Rare Unknown
Nervous system disorders	Headache Tremor	Very common1 Uncommon
Eye disorders	Cataract Glaucoma Visual blurring	Uncommon Rare4 Unknown4
Cardiac disorders	Palpitations Tachycardia Cardiac arrhythmia (including atrial fibrillation, supraventricular tachycardia, and extrasystoles) atrial fibrillation Angina pectoris	Uncommon Uncommon Rare Uncommon Uncommon
Respiratory system disorders	Nasopharyngitis Throat irritation Hoarseness/dysphonia Sinusitis Paradoxical bronchospasm	Very common2,3 Common Common Common1,3 Rare4
Skin and subcutaneous tissue disorders	Contusions	Common1,3
Musculoskeletal and connective tissue disorders	Muscle spasms Traumatic fractures Arthralgia Myalgia	Common Common Common Common
General disorders	Non-specific chest pain	Very rare

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

Pharmacologically expected side effects of β2-agonists, such as tremor, subjective palpitations, and headache, have been reported; however, these are usually transient and diminish with regular use.

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

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

The incidence of hoarseness and candidiasis can be reduced by rinsing the mouth and throat with water after using the inhaler. Symptomatic candidiasis can be treated with topical antifungal agents without discontinuing the use of the drug.

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, including hyperactivity and agitation.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach and sight of children. Do not freeze.

Packaging.

120 doses in an aluminium aerosol can with metering valve, plastic actuator with dose indicator, and dust cap. One can in an aluminium pouch with a silica gel desiccant bag, in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Cipla Ltd. (Unit II).

Manufacturer's address and site of manufacturing activity.

Plot Nos. L-139, S-103 and M-62, Verna Industrial Estate, IN - 403 722 Verna, Goa, India.