Flixotide evohalier

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLIXOTIDE EVOHALER (FLIXOTIDE EVOHALER)

Composition:

Active substance: fluticasone propionate;

1 dose contains fluticasone propionate 50 mcg or 125 mcg;

Excipient: propellant HFA 134a.

Pharmaceutical form. Pressurized metered-dose inhalation aerosol.

Main physicochemical characteristics: white or almost white suspension.

Pharmacotherapeutic group. Anti-asthmatic agents for inhalation use. Glucocorticoids. ATC code R03BA05.

Pharmacological properties.

Pharmacodynamics.

Fluticasone propionate, when administered by inhalation at recommended doses, exerts a pronounced glucocorticoid anti-inflammatory effect in the lungs. This results in reduction of both asthma symptoms and exacerbations, with fewer and less severe adverse effects compared to systemic administration of corticosteroids.

Pharmacokinetics.

The mean systemic bioavailability of Flixotide Evohaler, based on studies in healthy volunteers, was 28.6%. Systemic absorption occurs primarily via the respiratory tract, initially rapidly and then over a prolonged period. Any remaining portion of the inhaled dose may be swallowed.

Absolute oral bioavailability is very low (< 1%) due to incomplete gastrointestinal absorption and extensive first-pass metabolism. 87–100% of an oral dose is excreted in feces, with up to 75% eliminated as unchanged drug and inactive major metabolite.

Safety profile data

Toxicological studies revealed only effects typical of potent corticosteroids, but at doses many times higher than those used therapeutically. Studies investigating the effects of the drug on reproductive function and potential teratogenicity revealed no new findings. Fluticasone propionate has no mutagenic activity in vitro or in vivo. Animal studies demonstrated absence of carcinogenic potential, as well as lack of irritant and sensitizing properties.

Clinical characteristics.

Indications.

Prophylactic treatment of bronchial asthma

Adults

Mild asthma: patients requiring daily intermittent symptomatic treatment with bronchodilators.

Moderate asthma: patients with unstable asthma or worsening of condition despite existing prophylactic therapy or therapy with bronchodilators only.

Severe asthma: patients with severe chronic asthma and patients dependent on systemic corticosteroids for adequate symptom control. After initiation of inhaled fluticasone propionate, many such patients may substantially reduce or completely discontinue oral corticosteroid use.

Children

Prophylactic anti-asthmatic treatment, including cases where asthma symptom control has not been achieved with prior treatment using other anti-asthmatic agents.

Contraindications.

Hypersensitivity to any component of the drug.

Interaction with other medicinal products and other forms of interaction.

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 P450 3A4 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 in healthy volunteers using intranasal fluticasone propionate have shown that ritonavir (a potent inhibitor of cytochrome P450 3A4), administered at 100 mg twice daily, may increase plasma concentrations of fluticasone propionate by hundreds of times, leading to a significant reduction in serum cortisol concentration. Information regarding such interaction with inhaled fluticasone propionate is limited, but such an increase in plasma concentration of fluticasone propionate may occur. Cases of Cushing's syndrome and adrenal suppression have also been reported. Concomitant use of fluticasone propionate and ritonavir should be avoided, except when the benefit outweighs the risk of systemic corticosteroid effects.

In a small study conducted in healthy volunteers, the less potent CYP3A inhibitor ketoconazole increased fluticasone propionate concentrations by up to 150% after a single inhalation, resulting in a significant reduction in serum cortisol concentration compared to fluticasone propionate alone. Concomitant use with other potent CYP3A inhibitors, such as itraconazole, is also expected to increase systemic fluticasone propionate concentrations and the risk of systemic effects. Caution should be exercised, and prolonged use of such drug combinations should be avoided whenever possible.

Concomitant use of fluticasone propionate with other potent CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic adverse effects.

Other CYP3A4 inhibitors cause minimal (erythromycin) or slight (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reduction in serum cortisol concentration. Such combinations should be avoided unless the expected benefit outweighs the potential increased risk of systemic corticosteroid side effects; in such cases, patients should be monitored for systemic adverse effects.

Special precautions for use

Bronchial asthma should be treated according to a stepwise regimen, and the patient's condition should be regularly monitored both clinically and by assessing pulmonary function parameters.

The inhalation technique should be checked periodically to ensure that actuation of the inhaler coincides with inhalation, thus ensuring optimal delivery of the drug to the lungs.

The patient should be sitting or standing during inhalation, as the inhaler is designed for use in an upright position.

Sudden and progressive worsening of asthma control is life-threatening, and consideration should be given to increasing corticosteroid dosage. In such cases, patients should perform daily peak flow monitoring.

Flixotide Evohaler is not intended for relief of acute symptoms, for which short-acting bronchodilators should be used. Patients should be advised to always have medication available for the relief of acute asthma attacks.

Severe asthma requires continuous medical supervision, including assessment of pulmonary function parameters, due to the risk of acute asthma attacks and even fatal outcomes in such patients. Increased frequency of use or dosage of short-acting inhaled beta-2 agonists indicates progressive loss of asthma control. If short-acting bronchodilators become less effective or need to be used more frequently, the patient should consult a physician. In such cases, patients should undergo additional evaluation to determine the need for intensified anti-inflammatory therapy (e.g., increased doses of inhaled corticosteroids or initiation of a course of oral corticosteroids). Standard therapy for severe asthma exacerbation should be administered.

There have been isolated reports of increased blood glucose levels in both patients with diagnosed diabetes mellitus and in those without diabetes (see section "Adverse reactions"). This should be taken into account when prescribing Flixotide to diabetic patients.

As with other inhaled medications, paradoxical bronchospasm with rapidly worsening dyspnea may occur after inhalation. In such cases, Flixotide Evohaler should be discontinued, the patient should be evaluated, and alternative therapy should be considered if necessary.

When using inhaled corticosteroids, particularly at high doses and for prolonged periods, systemic effects may occur, although the likelihood is significantly lower than with oral corticosteroids. Systemic effects may manifest as Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineralization, and, in rare cases, psychiatric disorders, behavioral changes including psychomotor hyperactivity, sleep disturbances, restlessness, depression, and aggression (mainly in children). Therefore, it is important that the dose of inhaled corticosteroids be reduced to the lowest possible level that maintains effective control of asthma symptoms.

Prolonged use of high doses of inhaled corticosteroids may lead to adrenal suppression and acute adrenal crisis. Children under 16 years of age receiving fluticasone doses exceeding approved levels (usually ≥ 1000 mcg/day) are at particular risk. Acute adrenal crisis may be triggered by trauma, surgery, infections, or abrupt reduction in drug dosage. Symptoms are often nonspecific and may include anorexia, abdominal pain, weight loss, fatigue, headache, nausea, vomiting, decreased level of consciousness, hypoglycemia, and seizures. Additional systemic corticosteroids may be required during periods of stress or surgical procedures.

Regular monitoring of growth in children receiving long-term inhaled corticosteroid therapy is recommended. If growth retardation occurs, therapy should be re-evaluated with the aim of reducing the inhaled corticosteroid dose, if possible, to the lowest dose that maintains effective asthma symptom control. Consultation with a pulmonologist is also recommended.

Some patients may be more sensitive to inhaled corticosteroids than the majority of patients.

Drug delivery at doses exceeding 1000 mcg per day should preferably be administered using a spacer to reduce the risk of adverse effects in the oral cavity and throat. However, since the drug is primarily absorbed through the lungs, using a spacer in addition to the inhaler may increase drug delivery to the lungs. This should be taken into account, as it may potentially increase the risk of systemic side effects. Dose reduction may therefore be necessary (see section "Dosage and administration").

Treatment with inhaled fluticasone propionate may allow reduction or elimination of oral corticosteroid use. However, after switching patients from oral corticosteroids to inhaled fluticasone propionate, the risk of adrenal suppression may persist for a prolonged period. The extent of suppression in individual cases may require specialist evaluation.

Adrenal suppression should be considered in emergency situations, including surgery and other stress conditions, and appropriate corticosteroid therapy should be considered.

Inadequate treatment response or severe asthma exacerbation may require increased doses of Flixotide and, if necessary, systemic corticosteroids and/or antibiotics in case of infection.

Switching from systemic corticosteroid therapy to inhaled therapy may sometimes unmask allergic conditions such as allergic rhinitis or eczema previously controlled by systemic steroids. These allergic manifestations should be treated symptomatically with antihistamines and/or topical agents, including topical corticosteroids.

As with other inhaled corticosteroids, Flixotide Evohaler should be used with particular caution in patients with active or latent pulmonary tuberculosis.

Flixotide Evohaler treatment should not be stopped abruptly.

Transitioning patients previously treated with oral corticosteroids to inhaled therapy

Due to the potential for adrenal suppression, transitioning patients from oral corticosteroids to Flixotide Evohaler requires special attention, as recovery of adrenal function suppressed by long-term systemic corticosteroid therapy may take a prolonged time.

Patients who have received long-term or high-dose systemic corticosteroid therapy may have adrenal suppression. Adrenal function in such patients should be monitored regularly, and systemic corticosteroid doses should be reduced cautiously.

Gradual withdrawal of systemic corticosteroids should begin approximately one week after starting inhaled therapy. Dose reductions should correspond to the maintenance level of systemic corticosteroids and should be made at intervals of at least one week. Generally, for maintenance doses of prednisolone (or equivalent) of 10 mg/day or less, dose reductions should not exceed 1 mg/day at intervals of at least one week. For maintenance doses exceeding 10 mg/day of prednisolone, reductions greater than 1 mg/day may be allowed at intervals of at least one week, but with particular caution.

Some patients may experience nonspecific worsening of general condition during the transition period, despite maintained or even improved respiratory function. The transition from systemic corticosteroids to inhaled fluticasone propionate should continue unless objective signs of adrenal insufficiency occur.

Patients who have discontinued oral corticosteroids but still have impaired adrenal function should carry a special alert card indicating the need for additional systemic corticosteroids during stress situations, such as acute asthma attacks, respiratory infections, significant intercurrent illnesses, surgery, or trauma.

Ritonavir may significantly increase plasma concentrations of fluticasone propionate; therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, except when the benefit outweighs the risk of systemic corticosteroid effects. There is also an increased risk of systemic effects of fluticasone propionate when used concomitantly with CYP3A4 inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

Vision disorders

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 for evaluation of possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy, which has been reported after use of systemic and topical corticosteroids.

Use during pregnancy or breastfeeding

Fertility

There are no data on the effect on human fertility. Animal studies did not show any effect of fluticasone propionate on fertility.

Pregnancy

Human experience with use during pregnancy is limited.

When considering the use of the drug during pregnancy, the expected benefit to the mother should be weighed against the potential risk to the fetus. Results of 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.

Breastfeeding

It is currently unknown whether fluticasone propionate passes into breast milk; however, based on the pharmacological profile of the drug, this is unlikely. The drug may be used during breastfeeding only if the expected benefit to the mother outweighs the potential risk to the infant.

Ability to affect reaction speed when driving or operating machinery

Any such effect is unlikely.

Method of Administration and Dosage

The medication is intended for inhalation use only via the mouth.

Patients who have difficulty synchronizing breathing with actuation of the inhaler are advised to use a spacer device (an accessory designed to facilitate delivery of inhaled medications).

Patients should be informed that inhaled Fluticasone should be used regularly for prevention of symptoms, even during periods when asthma attacks are absent. Therapeutic effects typically begin within 4–7 days.

If short-acting bronchodilators become less effective or need to be used more frequently, patients should consult their physician.

The physician should be aware that fluticasone propionate is effective at a dose approximately half that of other inhaled corticosteroids. For example, 100 mcg of fluticasone propionate is approximately equivalent to 200 mcg of beclomethasone dipropionate (chlorofluorocarbon formulation) or budesonide.

The initial dose should correspond to the severity of the disease. The dosage may be increased until disease control is achieved or decreased to the lowest effective dose that maintains adequate control.

Adults and children aged 16 years and older: 100–1000 mcg twice daily, usually administered as 2 inhalations twice daily.

Due to the risk of systemic effects, doses exceeding 500 mcg twice daily should be prescribed only for adult patients with severe asthma, when improvement in lung function and/or symptom control is expected, and/or when reducing the use of oral corticosteroids (see sections "Special Warnings and Precautions" and "Adverse Reactions").

Typical initial dose for adults

For patients with mild asthma, the typical initial dose is 100 mcg twice daily. For moderate to severe persistent asthma, the initial dose may range from 250 to 500 mcg twice daily. If necessary, doses up to 1000 mcg twice daily may be prescribed. Such doses should only be prescribed by a specialist experienced in asthma management.

Dosage should be reduced to the lowest effective dose that maintains adequate disease control.

Typical initial dose for children aged 4 years and older: 50–100 mcg twice daily.

In many children, asthma is well controlled with doses of 50–100 mcg twice daily.

For patients who do not achieve adequate control with these doses, the dose may be increased to 200 mcg twice daily. The maximum dose for children is 200 mcg twice daily.

Dosage should be reduced to the lowest effective dose that maintains adequate disease control.

Administration of doses exceeding 1000 mcg (500 mcg twice daily) should be performed via a spacer to reduce the risk of local adverse effects in the mouth and throat (see section "Special Warnings and Precautions").

Special patient groups

Dosage adjustment is not required for elderly patients or for patients with hepatic or renal impairment.

Instructions for Inhaler Use

As with other inhaled medications, therapeutic efficacy may be reduced if the inhaler becomes cold. The inhaler must not be broken, punctured, or burned, even when empty.

Checking the Inhaler

Before first use or after a period of non-use exceeding one 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 that there are no foreign objects inside or outside the inhaler, including the mouthpiece.
3. Shake the inhaler vigorously to remove any foreign particles and to ensure uniform mixing of the contents.
4. Hold the inhaler vertically between the index finger and other fingers, with the index finger positioned on the base of the inhaler below the mouthpiece.
5. Breathe out fully, then place the mouthpiece between the teeth and seal lips around it without biting.
6. Begin inhaling slowly and deeply through the mouth, and simultaneously press down on the top of the inhaler to release a dose of Fluticasone, continuing to inhale slowly and deeply.
7. Hold the breath, remove the inhaler from the mouth, and release pressure on the top of the inhaler. Continue to hold the breath as long as possible.
8. If additional inhalations are required, 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 it into place until a click is heard.

IMPORTANT:

Perform steps 5, 6, and 7 without rushing. It is essential to begin inhaling as slowly as possible just before actuation. The first few times, practice in front of a mirror. If an aerosol mist appears at the top of the inhaler or around the sides of the mouth, repeat the steps starting from step 2. Immediately after use, cover the mouthpiece with the cap by pressing gently until a click is heard. As with other inhaled medications, therapeutic efficacy may be reduced if the canister is cold. Do not disassemble, puncture, or burn the canister, even after complete use.

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 with a dry cloth.
4. Replace the mouthpiece cap.

DO NOT IMMERSE THE METAL CANISTER IN WATER.

Children. For use in children aged 4 years and older.

Overdose

Acute overdose may occur with use of Fluticasone Evohaler at doses exceeding the recommended levels, manifesting as transient suppression of adrenal function. This does not require emergency treatment, as adrenal function typically recovers within several days, confirmed by measurement of plasma cortisol levels.

However, prolonged use of doses higher than recommended may result in significant suppression of adrenal function. There have been isolated reports of acute adrenal crises in children treated with higher-than-recommended doses (typically 1000 mcg or more) over prolonged periods (several months or years). Symptoms observed included hypoglycemia and consequences of loss of consciousness and/or convulsions. Situations that may potentially trigger an acute adrenal crisis include trauma, surgery, infection, or abrupt dose reduction.

In cases of overdose, therapy may continue at doses necessary to control asthma symptoms. Patients receiving doses higher than recommended should be under close medical supervision, and the dose should be reduced gradually (see section "Special Warnings and Precautions").

Adverse Reactions

The adverse reactions listed below are systematized by organ systems according to their frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data), including isolated case reports. Data on adverse reactions occurring very commonly, commonly, and uncommonly are primarily derived from clinical trials. Data on adverse reactions occurring rarely and very rarely are primarily obtained from spontaneous reports.

Infections and infestations

Very common: Oropharyngeal candidiasis.

Oropharyngeal candidiasis (thrush) may occur in some patients. To prevent this, patients should rinse their mouth with water after each use of Flixotide EVOHALER. If necessary, topical antifungal therapy may be prescribed during the entire treatment period, while continuing the use of Flixotide EVOHALER.

Common: Pneumonia may develop in patients with COPD.

In clinical trials of patients with COPD receiving fluticasone propionate at a dose of 500 mcg (see section "Adverse Reactions"), an increased incidence of pneumonia was reported. Physicians should be vigilant for the possible development of pneumonia in patients with COPD, as the clinical symptoms of pneumonia and COPD exacerbation often overlap.

Rare: Esophageal candidiasis.

Immune system

Hypersensitivity reactions have been reported, including:

Uncommon: Skin hypersensitivity reactions.

Very rare: Angioedema (mainly of the face and oropharynx), respiratory symptoms (dyspnea and/or bronchospasm), and anaphylactic reaction.

Eye disorders

Frequency not known: Visual disturbance.

Endocrine system

Very rare: Possible systemic effects, including (see section "Special Warnings and Precautions for Use") Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineralization, cataract, and glaucoma.

Metabolism and nutrition disorders

Very rare: Hyperglycemia (see section "Special Warnings and Precautions for Use").

Gastrointestinal system

Very rare: Dyspepsia.

Musculoskeletal system

Very rare: Arthralgia.

Psychiatric disorders

Very rare: Feeling of restlessness, sleep disorders, behavioral changes including hyperactivity and agitation (mainly in children).

Frequency not known: Depression, aggression (mainly in children).

Respiratory, thoracic and mediastinal disorders

Common: Hoarseness/dysphonia.

In some patients, inhaled fluticasone propionate may cause hoarseness. Rinsing the mouth with water immediately after inhalation may be beneficial.

Very rare: Paradoxical bronchospasm (see section "Special Warnings and Precautions for Use").

Frequency not known: Epistaxis (nasal bleeding).

Skin and subcutaneous tissue disorders

Common: Bruising.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 30°C. Do not freeze. Protect from direct sunlight. Keep out of reach of children.

Immediately after use, close the mouthpiece with the cap by pressing gently until a click is heard.

The canister is under pressure. Do not expose to temperatures above 50°C.

Packaging. 120 doses in an aerosol can with a metering valve; 1 can per carton.

Prescription status. Prescription only.

Manufacturer. Glaxo Wellcome Production, France.

Manufacturer's address and site of operation.

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

Date of latest revision.

APPROVED

Order of the Ministry of Health

of Ukraine

1. 01.2018 № 85

Registration Certificate

№ UA/7547/01/01

№ UA/7547/01/02

INSTRUCTION

for medical use of the medicinal product

FLIXOTIDE EVOHALER

(FLIXOTIDE EVOHALER)

Composition:

Active substance: fluticasone propionate;

1 dose contains fluticasone propionate 50 mcg or 125 mcg;

Excipient: propellant HFA 134a.

Pharmaceutical form. Pressurized metered-dose inhalation aerosol.

Main physicochemical properties: white or almost white suspension.

Pharmacotherapeutic group. Antiasthmatic agents for inhalation use. Glucocorticoids. ATC code R03BA05.

Pharmacological properties.

Pharmacodynamics.

Fluticasone propionate, when administered by inhalation at recommended doses, exerts a pronounced glucocorticoid anti-inflammatory effect in the lungs. This results in reduction of both asthma symptoms and exacerbations, with a lower incidence and severity of adverse reactions compared to systemic administration of corticosteroids.

Pharmacokinetics.

The mean systemic bioavailability of Fluticasone Evohaler in studies conducted in healthy volunteers was 28.6%. Systemic absorption occurs mainly via the respiratory tract, initially rapidly and then over a prolonged period. The remaining portion of the inhaled dose may be swallowed.

Absolute oral bioavailability is very low (< 1%) due to incomplete gastrointestinal absorption and extensive first-pass metabolism. 87–100% of the orally administered dose is excreted in feces, up to 75% as the parent compound and also as the inactive major metabolite.

Safety data

Toxicological studies showed only effects typical of potent corticosteroids, but at doses many times higher than those recommended for therapeutic use. Studies investigating the effects of the drug on reproductive function and potential teratogenic properties revealed no new findings. Fluticasone propionate does not exhibit mutagenic activity in vitro or in vivo. Animal studies demonstrated absence of carcinogenic potential, as well as lack of irritant and sensitizing properties.

Clinical characteristics.

Indications.

Prophylactic treatment of bronchial asthma

Adults

Mild asthma: patients requiring daily intermittent symptomatic treatment with bronchodilators.

Moderate asthma: patients with unstable asthma or worsening of condition despite existing prophylactic therapy or therapy with bronchodilators alone.

Severe asthma: patients with severe chronic asthma and patients dependent on systemic corticosteroids for adequate symptom control. After initiation of inhaled fluticasone propionate, many such patients may substantially reduce or completely discontinue oral corticosteroid use.

Children

Prophylactic anti-asthmatic treatment, including cases where asthma symptom control has not been achieved with previously administered anti-asthmatic medications.

Contraindications.

Hypersensitivity to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

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 P450 3A4 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 in healthy volunteers with intranasal fluticasone propionate have shown that ritonavir (a strong inhibitor of cytochrome P450 3A4), at a dose of 100 mg twice daily, may increase plasma concentrations of fluticasone propionate by hundreds of times, leading to a significant reduction in serum cortisol concentration. Information regarding such interaction with inhaled fluticasone propionate is limited, but such increased plasma concentrations of fluticasone propionate may occur. Cases of Cushing's syndrome and adrenal suppression have also been reported. Concomitant use of fluticasone propionate and ritonavir should be avoided, except when the benefit outweighs the risk of systemic corticosteroid effects.

In a small study conducted in healthy volunteers, the less potent CYP3A inhibitor ketoconazole increased fluticasone propionate concentrations by up to 150% after a single inhalation, resulting in a significant reduction in serum cortisol concentration compared to fluticasone propionate alone. Concomitant use with other strong CYP3A inhibitors, such as itraconazole, is also expected to increase systemic fluticasone propionate concentrations and the risk of systemic effects. Caution is advised, and prolonged use of such combinations should be avoided whenever possible.

Concomitant use of fluticasone propionate with other strong CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic adverse effects.

Other CYP3A4 inhibitors cause very slight (erythromycin) or slight (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reduction in serum cortisol concentration. Such combinations should be avoided unless the expected benefit outweighs the potential risk of increased systemic corticosteroid side effects; in such cases, patients should be monitored for signs of systemic adverse effects.

Special precautions for use

Bronchial asthma should be treated according to a stepwise regimen, and the patient's condition must be regularly monitored both clinically and by assessing pulmonary function parameters.

The inhalation technique should be checked periodically to ensure that actuation of the valve coincides with inhalation, thus ensuring optimal delivery of the drug to the lungs.

During inhalation, the patient should be in a sitting or standing position, as the inhaler is designed for use in the upright position.

Sudden and progressive worsening of asthma control is life-threatening and requires immediate consideration of increasing corticosteroid dosage. In such cases, patients should perform daily peak flow monitoring.

Fluticasone Evohaler is not intended for relief of acute symptoms, for which short-acting bronchodilators should be used. Patients must be warned to always have medication available for the relief of acute asthma attacks.

Severe asthma requires continuous medical supervision, including assessment of pulmonary function parameters, due to the risk of acute asthma attacks and even fatal outcomes in such patients. Increased frequency of use or dosage of short-acting inhaled beta-2 agonists indicates progressive loss of asthma control. If short-acting bronchodilators become less effective or need to be used more frequently, the patient should consult a physician. In such cases, patients should undergo additional evaluation to determine the need for intensified anti-inflammatory therapy (e.g., increasing inhaled corticosteroid doses or initiating a course of oral corticosteroids). Standard therapy for severe asthma exacerbation should be administered.

There have been isolated reports of increased blood glucose levels in both patients with diagnosed diabetes mellitus and in those without diabetes (see section "Adverse reactions"). This should be taken into account when prescribing Fluticasone to diabetic patients.

As with other inhaled medications, paradoxical bronchospasm with rapidly increasing dyspnea may occur after inhalation. In such cases, Fluticasone Evohaler should be discontinued, the patient should be evaluated, and alternative therapy should be considered if necessary.

When inhaled corticosteroids are used, particularly at high doses and for prolonged periods, systemic effects may occur, although the likelihood is significantly lower than with oral corticosteroids. Systemic effects may manifest as Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineralization, and, in rare cases, psychiatric disorders, behavioral changes including psychomotor hyperactivity, sleep disturbances, anxiety, depression, and aggression (mainly in children). Therefore, it is important that the dose of inhaled corticosteroids be reduced to the lowest possible dose that maintains effective control of asthma symptoms.

Prolonged use of high doses of inhaled corticosteroids may lead to adrenal suppression and acute adrenal crisis. Children under 16 years of age receiving fluticasone doses exceeding the approved doses (usually ≥ 1000 mcg/day) are at particular risk. Acute adrenal crisis may be provoked by trauma, surgery, infections, or abrupt reduction in drug dosage. Symptoms are often nonspecific and may include anorexia, abdominal pain, weight loss, fatigue, headache, nausea, vomiting, decreased level of consciousness, hypoglycemia, and seizures. Additional systemic corticosteroids may be required during periods of stress or surgical procedures.

Regular monitoring of growth in children receiving long-term inhaled corticosteroid therapy is recommended. If growth retardation occurs, therapy should be re-evaluated with the aim of reducing the inhaled corticosteroid dose, if possible, to the lowest dose that maintains effective asthma control. Consultation with a pulmonologist should also be considered.

Some patients may be more sensitive to inhaled corticosteroids than the majority of patients.

Drug delivery at doses exceeding 1000 mcg per day is recommended to be performed using a spacer to reduce the risk of adverse effects in the oral cavity and throat. However, since the drug is primarily absorbed through the lungs, using a spacer in addition to the inhaler may increase the amount of drug delivered to the lungs. This should be taken into account, as it may potentially increase the risk of systemic adverse effects. Dose reduction may therefore become necessary (see section "Dosage and administration").

The effect of inhaled fluticasone propionate allows minimization of the need for oral corticosteroids. However, after switching patients from oral corticosteroids to inhaled fluticasone propionate, the risk of adrenal suppression may persist for a prolonged period. The degree of suppression in individual cases may require evaluation by a specialist.

Adrenal insufficiency should be considered in emergency situations, including surgery and other stress conditions, and the need for appropriate corticosteroid therapy should be considered.

Inadequate treatment response or severe asthma exacerbation requires increasing the dose of Fluticasone and, if necessary, initiating systemic corticosteroids and/or antibiotics in case of infection.

Switching from systemic corticosteroid therapy to inhaled therapy may sometimes unmask allergic conditions such as allergic rhinitis or eczema, previously controlled by systemic corticosteroids. These allergic manifestations should be treated symptomatically with antihistamines and/or topical agents, including locally acting corticosteroids.

As with other inhaled corticosteroids, Fluticasone Evohaler should be used with particular caution in patients with active or latent pulmonary tuberculosis.

Treatment with Fluticasone Evohaler should not be stopped abruptly.

Transitioning patients previously treated with oral corticosteroids to inhaled therapy

Due to the potential for adrenal suppression, transitioning patients from oral corticosteroids to Fluticasone Evohaler requires special attention, as recovery of adrenal function suppressed by prolonged systemic corticosteroid therapy may take a long time.

Patients who have been treated with systemic corticosteroids for prolonged periods or at high doses may have suppressed adrenal function. Adrenal function in such patients should be monitored regularly, and systemic corticosteroid doses should be reduced cautiously.

Gradual withdrawal of systemic corticosteroids should begin approximately one week after initiating inhaled therapy. Dose reductions should correspond to the maintenance level of systemic corticosteroids and should be performed at intervals of at least one week. In general, for a maintenance prednisolone dose (or equivalent) of 10 mg per day or less, the dose reduction should not exceed 1 mg per day at intervals of at least one week. For maintenance prednisolone doses exceeding 10 mg per day, reductions greater than 1 mg per day may be allowed at intervals of at least one week, but with particular caution.

Some patients may experience nonspecific worsening of their condition during the transition period, despite maintained or even improved respiratory function. Transition from systemic corticosteroids to inhaled fluticasone propionate should continue unless objective signs of adrenal insufficiency appear.

Patients who have discontinued oral corticosteroid therapy but still have impaired adrenal function should carry a special alert card indicating the need for additional systemic corticosteroids during stress situations, such as acute asthma attacks, respiratory infections, significant intercurrent illnesses, surgery, or trauma.

Ritonavir may significantly increase plasma concentrations of fluticasone propionate; therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, except when the benefit outweighs the risk of systemic corticosteroid effects. There is also an increased risk of systemic effects of fluticasone propionate when used concomitantly with CYP3A4 inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

Vision 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 cataract, glaucoma, or rare conditions such as central serous chorioretinopathy, which has been reported after use of systemic and topical corticosteroids.

Use during pregnancy or breastfeeding

Fertility

There are no data on the effect on human fertility. Animal studies did not show any effect of fluticasone propionate on fertility.

Pregnancy

Human experience with use during pregnancy is limited.

The decision to prescribe the drug during pregnancy should be based on weighing the expected benefit to the mother against the potential risk to the fetus. Results of 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.

Breastfeeding

It is currently unknown whether fluticasone propionate passes into breast milk; however, based on the pharmacological profile of the drug, this is unlikely. The drug may be used during breastfeeding only if the expected benefit to the mother outweighs the potential risk to the infant.

Ability to affect reaction speed when driving or operating machinery

Any such effect is unlikely.

Method of Administration and Dosage

The medication is intended for inhalation use only via the mouth.

Patients who have difficulty synchronizing breathing with actuation of the inhaler are advised to use a spacer device (an accessory designed to facilitate delivery of inhaled medications).

Patients should be informed that inhaled Flixotide must be used regularly for disease prevention, even during periods when asthma attacks are absent. Therapeutic effects typically begin within 4–7 days.

If short-acting bronchodilators become less effective or need to be used more frequently, patients should consult their physician.

Physicians should be aware that fluticasone propionate is effective at a dose approximately half that of other inhaled corticosteroids. For example, 100 mcg of fluticasone propionate is roughly equivalent to 200 mcg of beclomethasone dipropionate (chlorofluorocarbon-containing formulation) or budesonide.

The initial dose should correspond to the severity of the disease. The dose may be increased until disease control is achieved or decreased to the lowest effective dose that maintains adequate control.

Adults and children aged 16 years and older: 100–1000 mcg twice daily, usually two inhalations twice daily.

Due to the risk of systemic effects, doses exceeding 500 mcg twice daily should be prescribed only for adult patients with severe bronchial asthma, when improvement in lung function and/or symptom control is expected, or when aiming to reduce or discontinue oral corticosteroids (see sections “Special Warnings and Precautions for Use” and “Adverse Reactions”).

Typical starting dose for adults

For patients with mild asthma, the typical starting dose is 100 mcg twice daily. For moderate persistent asthma and severe persistent asthma, the starting dose may range from 250 to 500 mcg twice daily. If necessary, doses up to 1000 mcg twice daily may be prescribed. Such doses should only be prescribed by a specialist experienced in asthma management.

Dosage should be reduced to the lowest effective dose that maintains adequate disease control.

Typical starting dose for children aged 4 years and older: 50–100 mcg twice daily.

In many children, asthma is well controlled with doses of 50–100 mcg twice daily.

For patients in whom the above doses are insufficient for disease control, the dose may be increased to 200 mcg twice daily. The maximum dose for children is 200 mcg twice daily.

Dosage should be reduced to the lowest effective dose that maintains adequate disease control.

Administration of doses exceeding 1000 mcg (500 mcg twice daily) should be performed via a spacer to reduce the risk of local adverse effects in the mouth and throat (see section “Special Warnings and Precautions for Use”).

Special patient groups

Dose adjustment is not required for elderly patients or for patients with hepatic or renal impairment.

Instructions for Inhaler Use

As with other inhaled medications, therapeutic effectiveness may be reduced if the canister becomes cold. The canister must not be broken, punctured, or incinerated, even when empty.

Inhaler Check

Before first use or after a period of non-use exceeding one 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 inhaler, including the mouthpiece, is free of foreign objects both inside and outside.
3. Shake the inhaler thoroughly to remove any foreign particles and to ensure uniform mixing of the contents.
4. Hold the inhaler vertically between the index and other fingers, with the thumb positioned at the base of the inhaler below the mouthpiece.
5. Breathe out fully, then place the mouthpiece between the teeth and seal lips around it without biting.
6. Begin inhaling slowly and deeply through the mouth, and at the same time press down on the top of the inhaler to release a dose of Flixotide, continuing to inhale slowly and deeply.
7. Hold the breath, remove the inhaler from the mouth, and release pressure from the top of the inhaler. Continue to hold the breath as long as comfortable.
8. If additional doses are required, 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 it into place until a click is heard.

IMPORTANT:

Perform steps 5, 6, and 7 without rushing. It is important to begin inhaling as slowly as possible just before actuation. For the first few uses, practice in front of a mirror. If an aerosol mist appears at the top of the inhaler or around the sides of the mouth, repeat the steps starting from step 2. Immediately after use, cover the mouthpiece with the cap by pressing gently until a click is heard. As with other inhaled medications, therapeutic effectiveness may be reduced if the canister is cold. Do not disassemble, puncture, or incinerate the canister, even after complete use.

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 with a dry cloth.
4. Replace the mouthpiece cap.

DO NOT IMMERSE THE METAL CANISTER IN WATER.

Children. For use in children aged 4 years and older.

Overdose

Acute overdose may occur with administration of Flixotide Evohaler at doses exceeding the recommended levels, leading to temporary suppression of adrenal gland function. This does not require emergency treatment, as adrenal cortical function recovers within several days, confirmed by measurement of plasma cortisol levels.

However, prolonged use of doses higher than recommended may result in significant suppression of adrenal function. There have been isolated reports of acute adrenal crises in children treated with doses above the recommended levels (typically 1000 mcg or higher) over prolonged periods (several months or years). Symptoms observed included hypoglycemia and consequences of loss of consciousness and/or seizures. Situations that may potentially trigger an acute adrenal crisis include trauma, surgery, infection, or abrupt dose reduction.

In cases of overdose, therapy may continue at doses sufficient to control asthma symptoms. Patients receiving doses higher than recommended should be under close medical supervision, and their dose should be tapered gradually (see section “Special Warnings and Precautions for Use”).

Side effects

The adverse reactions listed below are systematized by organs and systems according to their frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), and frequency not known (frequency cannot be estimated from the available data), including isolated reports. Data on adverse reactions occurring very commonly, commonly, and uncommonly are primarily based on clinical trials. Data on adverse reactions occurring rarely and very rarely are mainly obtained from spontaneous reports.

Infections and infestations

Very common: oral and pharyngeal candidiasis.

Oral and pharyngeal candidiasis (thrush) may occur in some patients. To prevent this, patients should rinse the mouth with water after using Flixotide Easi-Breathe. If necessary, a topical antifungal agent may be prescribed locally throughout the treatment period, while continuing the use of Flixotide Easi-Breathe.

Common: pneumonia in patients with COPD.

In clinical trials of patients with COPD receiving fluticasone propionate at a dose of 500 mcg (see section "Side effects"), an increased incidence of pneumonia was reported. Physicians should be vigilant regarding the possible development of pneumonia in patients with COPD, as the clinical symptoms of pneumonia and COPD exacerbation often overlap.

Rare: esophageal candidiasis.

Immune system

Hypersensitivity reactions have been reported with the following manifestations:

Uncommon: skin hypersensitivity reactions.

Very rare: angioedema (mainly of the face and oropharynx), respiratory symptoms (dyspnea and/or bronchospasm), and anaphylactic reaction.

Eye disorders

Frequency not known: visual disturbance.

Endocrine system

Very rare: possible systemic effects, including (see section "Special precautions") Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineralization, cataract, and glaucoma.

Metabolism and nutritional disorders

Very rare: hyperglycemia (see section "Special precautions").

Gastrointestinal system

Very rare: dyspepsia.

Musculoskeletal and connective tissue disorders

Very rare: arthralgia.

Psychiatric disorders

Very rare: feeling of restlessness, sleep disorders, behavioral changes including hyperactivity and agitation (mainly in children).

Frequency not known: depression, aggression (mainly in children).

Respiratory, thoracic and mediastinal disorders

Common: hoarseness/dysphonia.

In some patients, inhaled fluticasone propionate may cause hoarseness. In such cases, rinsing the mouth with water immediately after inhalation is beneficial.

Very rare: paradoxical bronchospasm (see section "Special precautions").

Frequency not known: epistaxis (nosebleeds).

Skin and subcutaneous tissue disorders

Common: bruising.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 30°C. Do not freeze. Protect from direct sunlight. Keep out of the reach of children.

Immediately after use, close the mouthpiece with the cap by pressing gently until a click is heard.

The canister is under pressure. Do not expose to temperatures above 50°C.

Packaging. 120 doses in an aerosol canister with a metering valve; 1 canister per carton.

Prescription status. Prescription only.

Manufacturer. Glaxo Wellcome S.A., Spain.

Manufacturer's address.

Avenida de Extremadura 3, Pol. Ind. Allendeduero, 09400 Aranda de Duero, Burgos, Spain.