Flixotide (Aerosol) Instructions for Use

Marketing Authorization Holder

GlaxoSmithKline Trading, JSC (Russia)

Manufactured By

Glaxo Wellcome, S.A. (Spain)

ATC Code

R03BA05 (Fluticasone)

Active Substance

Fluticasone (Rec.INN registered by WHO)

Dosage Forms

	Flixotide	Metered dose inhalation aerosol 50 mcg/1 dose: 120 dose inhalers
		Metered dose inhalation aerosol 125 mcg/1 dose: 60 dose or 120 dose inhalers
		Metered dose inhalation aerosol 250 mcg/1 dose: 60 dose or 120 dose inhalers

Dosage Form, Packaging, and Composition

Metered dose inhalation aerosol as a white to off-white suspension.

Excipients: 1,1,1,2-tetrafluoroethane.

120 doses – aluminum inhalers (1) with a dosing device – cardboard packs.

Metered dose inhalation aerosol as a white to off-white suspension.

Excipients: 1,1,1,2-tetrafluoroethane.

60 doses – aluminum inhalers (1) with a dosing device – cardboard packs.
120 doses – aluminum inhalers (1) with a dosing device – cardboard packs.

Metered dose inhalation aerosol as a white to off-white suspension.

Excipients: 1,1,1,2-tetrafluoroethane.

60 doses – aluminum inhalers (1) with a dosing device – cardboard packs.
120 doses – aluminum inhalers (1) with a dosing device – cardboard packs.

Clinical-Pharmacological Group

Inhaled corticosteroids

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases; other agents for inhalation administration used for the treatment of obstructive airway diseases; glucocorticosteroids

Pharmacological Action

Fluticasone propionate belongs to the group of topical glucocorticosteroids and, when administered by inhalation in recommended doses, has a pronounced anti-inflammatory and anti-allergic effect.

This leads to a reduction in the severity of symptoms and a decrease in the frequency of exacerbations of diseases accompanied by airway obstruction (bronchial asthma, chronic bronchitis, emphysema).

Fluticasone propionate inhibits the proliferation of mast cells, eosinophils, lymphocytes, macrophages, neutrophils, and reduces the production and release of inflammatory mediators and other biologically active substances – histamine, prostaglandins, leukotrienes, cytokines.

In COPD, the efficacy of inhaled fluticasone propionate (when used in combination with long-acting bronchodilators) on lung function has been confirmed, characterized by a reduction in the severity of disease symptoms, the frequency and severity of exacerbations, a decreased need for additional courses of oral glucocorticosteroids, and an improvement in the quality of life of patients compared to placebo.

In therapeutic doses, the effect on the hypothalamic-pituitary-adrenal system is insignificant, and this effect is not considered clinically significant.

The therapeutic effect after inhalation of fluticasone begins within 24 hours, reaches a maximum within 1-2 weeks or more after the start of treatment, and persists for several days after discontinuation.

Pharmacokinetics

Absorption

The absolute bioavailability of fluticasone propionate when administered as a metered dose inhalation aerosol in healthy volunteers is approximately 10.9%. In patients with chronic obstructive pulmonary disease (COPD) or bronchial asthma, the systemic exposure of the drug is less than in healthy volunteers.

Systemic absorption occurs primarily in the lungs, with initial rapid absorption followed by a slowdown.

A portion of the inhaled dose may be swallowed, but its systemic effect is minimal due to the drug’s poor solubility in water and intensive first-pass metabolism in the liver (the oral bioavailability of fluticasone propionate is less than 1%).

There is a direct relationship between the magnitude of the inhaled dose and the systemic effect of fluticasone propionate.

Distribution

Plasma protein binding is moderately high, at 91%.

Fluticasone propionate has a large steady-state V_d – about 300 L.

Metabolism

Fluticasone propionate is very rapidly cleared from the systemic circulation, mainly as a result of metabolism to an inactive carboxylic acid metabolite by the cytochrome P450 isoenzyme CYP3A4.

Since there is a possibility of increased systemic exposure to fluticasone propionate, caution should be exercised when co-administering with known CYP3A4 inhibitors.

Elimination

The pharmacokinetics of fluticasone propionate are characterized by high plasma clearance (1150 ml/min). T_1/2 is about 8 hours. Renal clearance is less than 0.2%. Less than 5% is excreted in the urine as a metabolite.

Indications

• Basic anti-inflammatory therapy for bronchial asthma in adults and children 1 year of age and older (including patients with severe disease who are dependent on systemic glucocorticosteroids);
• Treatment of chronic obstructive pulmonary disease in adults as an add-on therapy to long-acting bronchodilators (for example, to long-acting beta-agonists LABA).

ICD codes

Dosage Regimen

The Flixotide^® metered dose aerosol is intended for oral inhalation only.

Treatment with Flixotide^® aerosol is a method of prophylactic therapy; the drug must be used regularly, even in the absence of disease symptoms.

Patients who have difficulty using a metered dose inhalation aerosol are recommended to use a spacer.

No special dose adjustment is required for elderly individuals and patients with liver or kidney diseases.

Bronchial asthma

The therapeutic effect after using Flixotide^® occurs 4-7 days after the start of treatment.

In patients who have not previously used inhaled glucocorticosteroids, improvement may be noted as early as 24 hours after starting the drug.

If the patient feels that treatment with rapid-acting bronchodilators is becoming less effective, or requires more inhalations than usual, the doctor should pay special attention to this.

Adults and adolescents over 16 years: the recommended dose is 100-1000 mcg twice daily.

The initial dose of the drug depends on the severity of the disease: for mild bronchial asthma – 100-250 mcg twice daily, for moderate bronchial asthma – 250-500 mcg twice daily, for severe bronchial asthma – 500-1000 mcg twice daily.

Depending on the individual patient response, the initial dose of the drug can be increased until disease control is achieved or reduced to the minimum effective dose.

Children aged 4 years and older are recommended to use Flixotide^® containing 50 mcg of fluticasone propionate per dose.

The recommended dose is 50-200 mcg twice daily.

In most children, asthma control can be achieved using doses of 50-100 mcg twice daily.

In children with inadequately controlled bronchial asthma, it is possible to increase the dose to 200 mcg twice daily.

The initial dose of the drug depends on the severity of the disease.

Then, depending on the individual patient response, the initial dose of the drug can be increased until disease control is achieved or reduced to the minimum effective dose.

Children aged from 1 year to 4 years: the recommended dose is 100 mcg twice daily.

The drug is administered using an inhaler through a spacer with a face mask, for example, a “Babyhaler”.

The Flixotide^® metered dose aerosol is especially indicated for young children with frequent and prolonged attacks of bronchial asthma.

Diagnosis and treatment of bronchial asthma should be performed with regular patient examination by a doctor.

Chronic obstructive pulmonary disease

Adults the recommended dose is 500 mcg twice daily as an add-on to therapy with long-acting bronchodilators (for example, LABA).

It is recommended to use the Flixotide^® metered dose aerosol containing 250 mcg per dose.

To achieve the optimal effect, the drug is recommended to be used daily for 3-6 months.

If there is no clinical improvement after 3-6 months, a medical examination is necessary.

Adverse Reactions

Adverse reactions are listed according to the affected organs and systems and frequency of occurrence.

Frequency is defined as follows: very common >1/10, common >1/100 and <1/10, uncommon >1/1000 and <1/100, rare >1/10000 and <1/1000, and very rare <1/10000, including isolated cases.

Frequency categories were formed based on clinical studies of the drug and post-marketing surveillance.

Infections and infestations very common – oral and pharyngeal candidiasis (candidal stomatitis).

Some patients may develop oral and pharyngeal candidiasis.

In such cases, it is recommended to rinse the mouth and throat with water after inhalation.

Topical antifungal drugs can be used while continuing therapy with Flixotide^®.

Common – pneumonia in patients with COPD.

Immune system disorders (hypersensitivity reactions with the following manifestations have been described): uncommon – hypersensitivity skin reactions; very rare – angioedema (mainly facial and oropharyngeal edema), respiratory disorders (dyspnea and/or bronchospasm) and anaphylactic reactions.

Endocrine disorders (systemic effects are possible): very rare – Cushing’s syndrome, cushingoid symptoms, adrenal cortical suppression, growth retardation, decreased bone mineral density, cataract, glaucoma.

Metabolism and nutrition disorders very rare – hyperglycemia.

Psychiatric disorders very rare – anxiety, sleep and behavior disorders, including hyperactivity and irritability (mainly in children).

Respiratory, thoracic and mediastinal disorders common – hoarseness (some patients may experience hoarseness; it is recommended to rinse the mouth and throat with water immediately after inhalation); very rare – paradoxical bronchospasm.

Skin and subcutaneous tissue disorders common – bruising.

Contraindications

• Hypersensitivity to any component of the drug;
• Acute bronchospasm;
• Status asthmaticus (as a primary agent);
• Childhood (under 1 year).

Use with caution in patients with liver cirrhosis, glaucoma, hypothyroidism, systemic infections (bacterial, fungal, parasitic, viral), osteoporosis, pulmonary tuberculosis, pregnancy and lactation.

Use in Pregnancy and Lactation

Fertility

There are no data on the effect on human fertility.

Animal studies have not revealed any effect of fluticasone propionate on male or female fertility.

Pregnancy

Data on the use of the drug in pregnant women are limited.

The use of fluticasone propionate during pregnancy is acceptable only if the potential benefit to the mother outweighs the possible risk to the fetus.

Results from a retrospective epidemiological study did not find an increased risk of serious congenital malformations (SCM) after the use of fluticasone propionate compared to other inhaled corticosteroids during the first trimester of pregnancy.

Reproductive studies in animals have shown that at systemic exposure levels exceeding those observed with the use of recommended therapeutic inhaled doses, only effects characteristic of glucocorticosteroids are observed.

Breastfeeding period

The excretion of fluticasone propionate in human breast milk has not been studied.

When measurable plasma concentrations were obtained in laboratory rats after subcutaneous administration of the drug during lactation, fluticasone propionate was also detected in breast milk.

However, after inhalation of fluticasone propionate in recommended doses, its plasma concentrations in patients are likely to be low.

The use of the drug during breastfeeding is acceptable only if the potential benefit to the mother outweighs the possible risk to the child.

Use in Hepatic Impairment

No dose adjustment is required for patients with impaired liver function.

Use in Renal Impairment

No dose adjustment is required for patients with impaired renal function.

Pediatric Use

Contraindication: children under 1 year of age.

In children over 4 years of age, it is recommended to use the aerosol containing 50 mcg of fluticasone propionate per dose.

It is recommended to prescribe 50-100 mcg twice daily.

The initial dose of the drug depends on the severity of the disease.

Then, depending on the individual patient’s response to treatment, the initial dose can be increased until a clinical effect appears or reduced to the minimum effective dose.

Children aged from 1 year to 4 years are recommended to be prescribed 100 mcg twice daily.

Younger children require higher doses of Flixotide compared to older children due to reduced drug delivery during inhalation (smaller bronchial lumen, use of a spacer, intensive nasal breathing in young children).

The drug is administered using an inhaler through a spacer with a face mask (for example, a “Babyhaler”).

The Flixotide metered dose aerosol is especially indicated for young children with severe bronchial asthma.

Geriatric Use

No dose adjustment is required for elderly individuals.

Special Precautions

An increased frequency of use of inhaled short-acting beta₂-agonists to control asthma symptoms indicates a worsening of disease control.

In such a case, the patient’s treatment plan requires revision.

Sudden and progressive worsening of asthma control is a potentially life-threatening condition for the patient and requires an increase in the dose of glucocorticosteroids.

Patients at risk may be prescribed daily peak flow measurements.

It is not recommended to abruptly discontinue treatment with Flixotide^®.

Particular caution should be exercised when treating patients with active or inactive forms of pulmonary tuberculosis with inhaled glucocorticosteroids.

It is recommended to check whether the patient can use the inhaler correctly to ensure that the inhaler is activated synchronously with inhalation to ensure optimal delivery of the active substance to the lungs.

With long-term use of any inhaled glucocorticosteroids, especially in high doses, systemic effects may occur; however, the likelihood of their development is significantly lower than with oral glucocorticosteroids.

Possible systemic effects include Cushing’s syndrome, cushingoid symptoms, adrenal suppression, decreased bone mineral density, growth retardation in children and adolescents, cataract, glaucoma.

Therefore, it is especially important that, upon achieving a therapeutic effect, the dose of inhaled glucocorticosteroids is reduced to the minimum effective dose that allows control of the disease.

It is recommended to regularly monitor the growth dynamics of children receiving inhaled glucocorticosteroids for a long time.

The possibility of adrenal insufficiency in emergency situations (including surgery), as well as during planned interventions that may cause stress, especially in patients taking high doses of glucocorticosteroids for a long time, should always be considered.

In this case, the need for additional prescription of glucocorticosteroids should be decided depending on the clinical situation (see section “Overdose”).

Due to possible adrenal insufficiency, special caution should be exercised and adrenal cortical function should be regularly monitored when transferring patients who have been taking oral glucocorticosteroids to treatment with fluticasone propionate in the form of an inhalation aerosol.

Discontinuation of systemic glucocorticosteroids while taking fluticasone propionate in the form of an inhalation aerosol should be carried out gradually, and patients should carry a card indicating that they may require additional glucocorticosteroids during periods of stress.

When transferring patients from systemic glucocorticosteroids to inhalation therapy, concomitant allergic diseases (for example, allergic rhinitis, eczema) that were previously suppressed by systemic drugs may also worsen.

In such situations, symptomatic treatment with antihistamines and/or topical agents, including topical glucocorticosteroids, is recommended.

As with other inhalation therapy, there is a possibility of paradoxical bronchospasm with immediate worsening of shortness of breath after inhalation.

To relieve this attack, immediate use of a rapid-acting and short-acting inhaled bronchodilator is necessary.

Inhalation of fluticasone propionate should be stopped immediately, the patient’s condition should be assessed, and, if necessary, alternative therapy should be prescribed.

As with most inhalation agents in aerosol packaging, the effect decreases when the canister is cold.

There are very rare reports of increased blood glucose concentrations, and this should be kept in mind when prescribing fluticasone propionate to patients with diabetes mellitus.

An increase in the incidence of pneumonia has been registered in patients with COPD receiving fluticasone propionate at a dose of 500 mcg.

The possibility of pneumonia in such patients should be kept in mind, since the clinical signs of pneumonia and exacerbation of the underlying disease may often coincide.

Effect on the Ability to Drive Vehicles and Mechanisms

The effect of fluticasone propionate on the ability to drive a car and operate machinery requiring increased concentration is unlikely.

Overdose

Symptoms Acute overdose of the drug may lead to temporary suppression of the hypothalamic-pituitary-adrenal system function, which usually does not require emergency therapy, as adrenal cortex function recovers within a few days. With long-term use of doses exceeding the recommended ones, significant suppression of adrenal cortex function is possible. Very rare reports have been received of acute adrenal crisis developing in children who received a dose of fluticasone propionate of 1000 mcg/day and higher for several months or years. Such patients experienced hypoglycemia, depressed consciousness, and convulsions. Acute adrenal crisis can develop against the background of the following conditions: severe trauma, surgery, infections, a sharp reduction in the dose of fluticasone propionate.

Treatment Monitoring of patients receiving high doses is necessary, as well as a gradual reduction in the dose of fluticasone propionate.

Drug Interactions

With the inhalation route of administration of fluticasone propionate, its plasma concentrations are very low due to active first-pass metabolism and high systemic clearance in the intestine and liver, involving cytochrome P450 3A4 system enzymes. Thus, clinically significant drug interactions of fluticasone propionate are unlikely.

A drug interaction study in healthy volunteers showed that ritonavir (a highly active cytochrome P450 3A4 inhibitor) can significantly increase the plasma concentration of fluticasone propionate, which accordingly leads to a decrease in serum cortisol concentration. Within the framework of post-registration use, clinically significant drug interactions have been observed in patients receiving fluticasone propionate intranasally or by inhalation concomitantly with ritonavir, leading to systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression. Therefore, concomitant use of the drug ritonavir and fluticasone propionate should be avoided, except in cases where the potential benefit to the patient outweighs the possible risk of systemic corticosteroid side effects.

Studies of other cytochrome P450 3A4 inhibitors demonstrated insignificant (erythromycin) and small (ketoconazole) increases in the systemic exposure to fluticasone propionate without any noticeable decrease in serum cortisol concentration. Nevertheless, caution should be exercised when co-administering potent cytochrome P450 3A4 inhibitors (e.g., ketoconazole), as there is a possibility of an increase in the plasma concentration of fluticasone propionate.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F); do not freeze or expose to direct sunlight.

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

RU/FLT/0003/16 23.12.16

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.