Fluticasone

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUTIXON

Composition:

Active substance: fluticasonum;

1 capsule contains 125 mcg or 250 mcg of fluticasone propionate;

Excipients: anhydrous lactose, lactose monohydrate.

Pharmaceutical form. Powder for inhalation, hard capsules.

Main physicochemical properties:

125 mcg capsules: transparent two-piece hard gelatin capsules of size "3" containing white to almost white powder;

250 mcg capsules: two-piece hard gelatin capsules of size "3" with a black ring, containing white to almost white powder.

Pharmacotherapeutic group. Other drugs for obstructive airway diseases. Inhaled glucocorticoids. ATC code R03BA05.

Pharmacological properties.

Pharmacodynamics.

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

Pharmacokinetics.

The absolute bioavailability of fluticasone propionate after inhaled administration ranges from 12% to 26% of the nominal dose, depending on the type of inhaler used.

Systemic absorption occurs primarily via the respiratory tract, initially rapidly and then over a prolonged period. The portion of the inhaled dose deposited in the mouth is swallowed, resulting in minimal systemic effect due to the low water solubility of fluticasone propionate and extensive presystemic metabolism, leading to an oral bioavailability of less than 1%.

87–100% of the orally ingested dose is excreted in feces, with up to 75% eliminated unchanged and the remainder as an inactive metabolite.

Preclinical safety 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 shown no mutagenic activity in vitro or in vivo. Animal studies demonstrated no carcinogenic potential, as well as no irritant or sensitizing properties.

Clinical characteristics.

Indications.

Prophylactic treatment of bronchial asthma

Adults

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

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 to achieve adequate symptom control. After initiation of inhaled fluticasone propionate, many of these patients may substantially reduce or completely discontinue oral corticosteroid therapy.

Chronic obstructive pulmonary disease (COPD).

Fluticasone propionate is indicated for the treatment of COPD in combination with a long-acting β2-agonist.

For use in this indication, fluticasone propionate must be administered by inhalation at a dose of 250 mcg or 500 mcg.

Children

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

Contraindications. Hypersensitivity to the active substance or to any of the excipients 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 mcg 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. When used concomitantly with other strong CYP3A inhibitors such as itraconazole, increased systemic fluticasone propionate concentrations and risk of systemic effects are also expected. Caution is advised, and prolonged use of such combinations should be avoided whenever possible.

Studies have shown that other cytochrome P450 3A4 inhibitors produce very minor (erythromycin) or minor (ketoconazole) increases in systemic exposure to fluticasone propionate, without notable reduction in serum cortisol concentration. Nevertheless, co-administration with strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole) should be performed with caution, as systemic exposure to fluticasone propionate may potentially increase.

Concomitant administration of glucocorticoids and CYP3A inhibitors, including products containing cobicistat, is expected to increase the risk of systemic adverse reactions. Such combinations should be avoided unless the benefit outweighs the increased risk of systemic side effects associated with glucocorticoid use; in such cases, patients should be monitored for systemic glucocorticoid effects.

Potential systemic effects include: Cushing's syndrome, Cushingoid appearance, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract, and glaucoma.

Special precautions for use.

Bronchial asthma should be treated according to a stepwise management plan, and the patient's condition should be monitored regularly 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.

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

Flutixone is not intended for relief of acute symptoms; short-acting bronchodilators should be used for this purpose. Patients should be warned to always have medication available for the treatment of acute asthma attacks.

Severe asthma requires continuous medical supervision, including assessment of pulmonary function, due to the risk of acute asthma attacks and even fatal outcomes in such patients. Increased frequency and dosage of short-acting inhaled β2-agonists indicate a 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 situations, 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). During severe asthma exacerbations, standard treatment for this condition 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 Flutixone to diabetic patients.

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

When inhaled corticosteroids are used, especially 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, cataract, glaucoma, 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 on long-term inhaled corticosteroid therapy is recommended. If growth retardation occurs, therapy should be reviewed with the aim of reducing the inhaled corticosteroid dose, if possible, to the lowest dose that maintains effective asthma control. Additional consultation with a pulmonologist is also necessary.

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

Delivery of doses exceeding 1000 mcg per day is recommended to be performed using a spacer device 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 be necessary (see section "Dosage and administration").

Treatment with inhaled fluticasone propionate may allow minimization of the need for oral corticosteroids. However, the risk of adverse effects remains for some time in patients previously treated with oral corticosteroids. The degree of adrenal suppression in individual cases may require specialist evaluation.

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

Inadequate treatment response or severe asthma exacerbation may require increasing the dose of Flutixone and, if necessary, adding systemic corticosteroids and/or antibiotics in the presence 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 medications, including topical corticosteroids.

As with other inhaled corticosteroids, Flutixone should be prescribed with particular caution in patients with active or latent pulmonary tuberculosis.

Treatment with Flutixone should not be discontinued abruptly.

Pneumonia in patients with COPD

In patients with COPD receiving inhaled corticosteroids, there have been reports of increased incidence of pneumonia, including pneumonia requiring hospitalization. Some evidence suggests an increased risk of pneumonia with higher corticosteroid doses, although this has not been consistently demonstrated in all studies.

There are no definitive clinical data showing differences among inhaled corticosteroid-containing products regarding the risk of pneumonia.

Physicians should closely monitor patients with COPD for possible pneumonia, as clinical symptoms of such infections often overlap with COPD exacerbations.

Risk factors for pneumonia in patients with COPD include tobacco smoking, advanced age, low body mass index (BMI), and severe COPD.

Transitioning patients from oral corticosteroids to inhaled therapy.

Due to the potential for adrenal suppression, transitioning patients from oral corticosteroids to Flutixone 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 corticosteroids 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 initiating Flutixone. 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/day or less, the dose should not be reduced by more than 1 mg/day at intervals of at least one week. For maintenance prednisolone doses exceeding 10 mg/day, reductions greater than 1 mg/day may be permitted 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 stable or even improved respiratory function. The transition from systemic corticosteroids to inhaled fluticasone propionate should be continued 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 supplemental systemic corticosteroids during stressful 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").

Visual disturbances. Visual disturbances may occur following systemic or local use of corticosteroids. If a patient experiences symptoms such as blurred vision or other visual problems, an ophthalmological evaluation should be performed to identify possible causes such as cataract, glaucoma, or rare conditions such as central serous chorioretinopathy (CSCR), which has been reported after both systemic and topical corticosteroid use.

Use during pregnancy or breastfeeding.

Fertility

There are no data on the effect of fluticasone propionate 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 this period, the expected benefit to the mother should be weighed against the potential risk to the fetus. 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.

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.

The use of Flutixone does not affect reaction speed when driving or operating machinery.

Dosage and Administration

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

Patients should be informed that Flutixone should be used regularly for the prevention of asthma attacks, even during symptom-free periods. The onset of therapeutic effect is observed within 4–7 days.

If the efficacy of short-acting bronchodilators decreases or their use becomes more frequent, patients should consult their physician.

The initial dose should be based on the severity of the disease.

Bronchial Asthma

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

Due to the risk of systemic effects, doses exceeding 500 mcg twice daily should be prescribed only to 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 for Use" and "Adverse Reactions").

Typical initial doses for adults and children aged 16 years and older

• For mild asthma: 100–250 mcg twice daily.
• For moderate asthma: 250–500 mcg twice daily.
• For severe asthma: 500–1000 mcg twice daily.

Fluticasone propionate doses must be individually adjusted for each patient.

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

After improvement is achieved, the dose should be reduced to the lowest effective dose that maintains control.

It should be noted that fluticasone propionate is effective at approximately half the dose of other inhaled corticosteroids. For example, 100 mcg of fluticasone propionate is approximately equivalent to 200 mcg of beclomethasone dipropionate (CFC-containing formulation) or budesonide.

Chronic Obstructive Pulmonary Disease (COPD)

500 mcg twice daily in combination with a long-acting β2-agonist. The medication should be used daily for optimal benefit, which may take three to six months. If insufficient improvement is observed, the patient should be re-evaluated.

Special Patient Groups

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

Instructions for Inhaler Use

1. Remove the mouthpiece cap from the inhaler.
2. Holding the inhaler by the lower part, open it by turning the mouthpiece (upper part) in the direction of the arrow.
3. Place the capsule into the capsule-shaped chamber located in the lower part of the inhaler. The capsule should be removed from its packaging immediately before use.
4. Close the mouthpiece by returning it to the closed position.
5. Press both buttons on the lower part of the inhaler fully down (only once!), while holding the inhaler in an upright position.

WARNING! At this moment, the capsule may rupture, and small fragments may enter the mouth or throat. This is harmless. The risk of capsule rupture is minimized if the capsule is pierced only once, storage conditions are followed, and the patient opens the capsule immediately before use.

6. Breathe out deeply.
7. Place the mouthpiece in the mouth, tilt the head slightly backward, close lips tightly around the mouthpiece, and inhale quickly and evenly in one breath. At this moment, the capsule begins to rotate inside the inhaler chamber, dispersing the powder, accompanied by a characteristic sound. If no sound is heard, the capsule may be stuck. In this case, open the inhaler and free the capsule. Do not attempt to free the capsule by repeatedly pressing the buttons.
8. Upon hearing the characteristic sound (a buzzing), hold the breath as long as possible without discomfort, then remove the inhaler from the mouth and exhale. Then open the inhaler and check whether any powder remains in the capsule. If powder remains, repeat steps 6–8.
9. Open the inhaler, remove the empty used capsule, return the mouthpiece to the closed position, and replace the mouthpiece cap.

Cleaning the Inhaler: To remove powder residue, wipe the mouthpiece and capsule chamber with a dry cloth or clean soft brush.

All unused medication or waste should be disposed of according to local regulations.

Children: This medication at the specified dosage can be used in children aged 16 years and older.

Overdose

Acute overdose may occur when Flutixone is used at doses exceeding the recommended levels, resulting in temporary suppression of adrenal gland function. This does not require emergency treatment, as adrenal cortex function recovers within several days, confirmed by plasma cortisol level measurements.

However, prolonged use of doses higher than recommended may lead to significant suppression of adrenal function. Isolated reports describe 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, infections, or a sudden reduction in dose.

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 gradually reduced (see section "Special Warnings and Precautions for Use").

Adverse reactions

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

Infections and infestations

Very common: oral and pharyngeal candidiasis.

Oral and pharyngeal candidiasis (fungal infection) may occur in some patients. To prevent this, patients should rinse the mouth with water after each use of Flutixone. If necessary, a topical antifungal agent should be prescribed throughout the treatment period, while continuing Flutixone therapy.

Common: increased risk of pneumonia in patients with COPD.

Rare: esophageal candidiasis.

Immune system disorders

Hypersensitivity reactions have been reported, including the following manifestations:

Uncommon: skin hypersensitivity reactions.

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

Endocrine system disorders

Systemic effects may occur (see section "Special precautions for use"), including:

Very rare: 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 precautions for use").

Gastrointestinal disorders

Very rare: dyspepsia.

Musculoskeletal and connective tissue disorders

Very rare: arthralgia.

Psychiatric disorders

Very rare: feelings of anxiety, sleep disturbances, behavioral changes including hyperactivity and agitation (mainly in children).

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

Respiratory, thoracic and mediastinal disorders

Common: hoarseness.

Inhaled fluticasone propionate may cause hoarseness in some patients. Rinsing the mouth with water immediately after inhalation may help prevent this.

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

Frequency not known: epistaxis (nosebleeds).

Skin and subcutaneous tissue disorders

Common: bruising.

Eye disorders

Frequency not known: blurred vision.

Shelf life. 2 years.

Storage conditions. Store below 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 capsules in a blister; 6 blisters or 12 blisters supplied with an inhaler in a cardboard box.

Prescription status. Prescription only.

Manufacturer. JSC "Adamed Pharma"

Manufacturer's name and address of the place of business.

ul. Marsz. J. Piłsudskiego 5, 95-200 Pabianice, Poland.