Fluticasone - instructions for use, dose, side effects, contraindications

Fluticasone propionate is a substance with a strong anti-inflammatory effect. With intranasal administration, there is no marked systemic effect and oppression of the hypothalamic-pituitary-adrenal system.

Interaction with intracellular glucocorticoid receptors leads to the formation of dimers of the glucocorticoid-glucocorticoid receptor complex. The steroid hormone complex with the receptor is transported to the nucleus of the cell. In the nucleus this complex interacts with effector elements localized on the acceptor sites of the chromatin (genes). As a result of the interaction, stimulation or inhibition of gene expression occurs; this leads to a change in the synthesis of matrix RNA and proteins. Anti-inflammatory effect is due to several factors:

1. The drug induces the synthesis of lipocortin, which inhibits the activity of phospholipase A2.Inhibition of phospholipase-mediated A2 hydrolysis of membrane phospholipids of damaged tissues prevents the formation of arachidonic acid. The disruption of the formation of arachidonic acid actually means inhibition of the synthesis of prostaglandins, since arachidonic acid is a substrate for further metabolism along the cyclooxygenase pathway, and also along the lipoxygenase pathway, with appropriate inhibition of leukotriene synthesis.

2. The anti-inflammatory effect of glucocorticoids is potentiated by their ability to inhibit the expression of COX-2 genes, which also leads to a decrease in the synthesis of prostaglandins in the inflammatory focus, including pro-inflammatory prostaglandins E2 and I2.

3. Prednisolone inhibits the expression of molecules of intercellular adhesion in the endothelium of blood vessels, violating the penetration of neutrophils and monocytes into the focus of inflammation. After the introduction of glucocorticoids, an increase in the concentration of neutrophils in the blood (due to their entry from the bone marrow and the restriction of migration from the blood vessels) is noted. This causes a decrease in the number of neutrophils in the site of inflammation.

Glucocorticoids inhibit the transcription of cytokine genes that stimulate the inflammatory and immune response (IL-1, IL-2, IL-6, IL-8), as well as tumor necrosis factor (and some others).

Suppresses the proliferation of mast cells, eosinophils, lymphocytes, macrophages, neutrophils; reduces the production of inflammatory mediators and other biological active substances (histamine, prostaglandins, leukotrienes, cytokines) during the early and late phase of the allergic reaction. Fluticasone propionate has a quick anti-inflammatory effect on the nasal mucosa, and its antiallergic effect is manifested as early as 2-4 hours after the first application. Reduces sneezing, itching in the nose, runny nose, stuffy nose, discomfort in the sinuses and a feeling of pressure around the nose and eyes. In addition, it alleviates eye symptoms associated with allergic rhinitis. Reduction in the severity of symptoms (especially nasal congestion) persists for 24 hours after a single injection of a spray at a dose of 200 μg. Fluticasone propionate improves the quality of life of patients, including physical and social activity.

Pharmacokinetics:

Suction

After intranapachnogo administration of fluticasone propionate at a dose of 200 mcg per day, the maximum equilibrium concentrations in the plasma are not quantitatively determined in the majority of patients (less than 0.01 ng / ml). The highest plasma concentration was recorded at 0.017 ng / ml. Direct absorption from the nasal cavity is unlikely due to low water solubility and the ingestion of most of the drug. Absolute oral bioavailability is low (less than 1%) as a result of a combination of incomplete absorption from the gastrointestinal tract and active metabolism during the first passage through the liver. The overall systemic absorption is, therefore, extremely low.

Distribution

Fluticasone propionate has a large volume of distribution in the equilibrium state (approx. 318 liters). The association with plasma proteins is high (91%).

Metabolism

Fluticasone propionate is excreted rapidly from the systemic blood flow mainly through metabolism in the liver with the formation of an inactive carboxylic acid via the cytochrome P450 cytochrome P450 isoenzyme CYP3A4. Metabolism of the swallowed fraction of fluticasone propionate during the first passage through the liver occurs in the same way.

Excretion

Elimination of fluticasone propionate is linear in the dose range from 250 to 1000 μg and is characterized by a high plasma clearance (1.1 l / min). The maximum plasma concentration is reduced to approximately 98% within 3-4 hours, and only at very low plasma concentrations a final half-life of 7.8 hours was observed. The renal clearance of fluticasone propionate is negligible (less than 0.2%), and the inactive metabolite - carboxylic acid is less than 5%. Fluticasone propionate and its metabolites are mainly excreted with bile through the intestine.

Indications:

Bronchial asthma (basic anti-inflammatory therapy) in adults and children 1 g and older (including those with a severe course of the disease, with dependence on systemic glucocorticosteroids), chronic obstructive pulmonary disease in adults.

Seasonal and all-the-year-round allergic rhinitis (prevention and treatment).

Atopic dermatitis, eczema, diffuse neurodermatitis, psoriasis, simple chronic lichen (limited neurodermatitis), lichen planus, contact dermatitis (simple and allergic), discoid lupus erythematosus, erythroderma (in addition to treatment with systemic glucocorticoids), insect bites, red sweats , seborrheic dermatitis.

ICD-10

X.J30-J39.J30.1 Allergic rhinitis caused by pollen of plants

X.J30-J39.J30.2 Other seasonal allergic rhinitis

X.J30-J39.J30.3 Other allergic rhinitis

X.J30-J39.J30.4 Allergic rhinitis, unspecified

X.J40-J47.J42 Chronic bronchitis, unspecified

X.J40-J47.J45 Asthma

Contraindications:

With inhalation application: hypersensitivity, acute bronchospasm, asthmatic status (as a primary means), bronchitis of non-astatic nature.

With intranasal application: hypersensitivity, fungal, bacterial and viral infections of the respiratory system, pulmonary tuberculosis, pregnancy (drops), breast-feeding.

With external application: hypersensitivity, rosacea, acne vulgaris, perioral dermatitis; perianal and genital itching, primary skin lesions of bacterial, viral and fungal etiology, children's age (for cream - up to 1 year, for ointment - up to 6 months).

Carefully:

For inhalation use: cirrhosis of the liver, glaucoma, hypothyroidism, systemic infections (bacterial, fungal, parasitic, viral), osteoporosis, pulmonary tuberculosis, pregnancy, breast-feeding.

With intranasal application: recent surgical interventions in the nasal cavity, recent trauma to the nose.

For external use: glaucoma, severe hepatic insufficiency, hypothyroidism, recently transferred myocardial infarction, bacterial, fungal, parasitic and viral infections (including amoebiasis, tuberculosis, herpes of the eyes), pregnancy, breast-feeding.

Pregnancy and lactation:

Recommendations for FDA - Category C. A means of choice for treatment during pregnancy in the US due to the large clinical experience of its use. Standard doses of inhaled glucocorticoids, as a rule, do not cause abnormalities on the part of the fetus. Qualitative and well-controlled studies on humans have not been conducted. In pharmacological doses can cause placental insufficiency, deficiency of fetal body weight, stillbirth. Teratogenic effect is not confirmed. Studies in animals have revealed an increase in the frequency of cleft palate, placental insufficiency, spontaneous abortion and delayed intrauterine development of the fetus. In newborns whose mothers received inhaled glucocorticoids during pregnancy, adrenal insufficiency should be excluded.

There is no information on the penetration into breast milk. When inhaled, concentrations often do not reach the detection limit in breast milk. To decide on the use during breastfeeding on the basis of a comparison of risk and benefit.

Dosing and Administration:

Bronchial asthma. Basic therapy (varying degrees of severity, 100-1000 mcg per day) (with cancellation or reduction of systemic glucocorticoid dose up to 2000 mcg per day).

Inhalations for adults and adolescents older than 16 years - the initial dose at a mild degree of 100-250 mcg 2 times a day, with an average degree of 250-500 mcg 2 times a day, with a severe degree - 500-1000 mcg 2 times a day.

Inhalation for children older than 4 years - 50-100 mcg 2 times a day, children 1 year-4 years - 100 mcg 2 times a day (younger children, in comparison with older children, require higher doses due to difficult entry of the substance into the lungs Inhalations: intense nasal breathing, less bronchus clearance, use of a spacer).

Chronic obstructive pulmonary disease (500 mcg twice a day for 3 years, slowing the progression of the disease from moderate to severe).

Seasonal and year-round allergic rhinitis (prevention and treatment).

Intranasal to adults and children 12 years and older for 100 mcg in each nasal passage 1 time per day (preferably in the morning), sometimes 2 times a day. The maximum daily dose of 200 mcg in each nasal passage.

Intranasal to children 4-11 years old, 50 micrograms per each nasal passage 1 time per day. The maximum daily dose of 100 mcg in each nasal passage.

Use in children.

Inflammatory skin diseases such as eczema, non-responding to weaker glucocorticoids, psoriasis.

Locally. 1 year-18 years - apply a thin layer 1-2 times a day.

Bronchial asthma, standard doses.

Inhalation. 1 month-12 years - in a dose of 50-100 mcg 2 times a day. 12-18 years - in a dose of 50-200 mcg 2 times a day.

Bronchial asthma, high doses.

Inhalation. 1 month-12 years - in a dose of 100-200 mkg 2 times a day. 12-18 years - in a dose of 200-500 mcg 2 times a day.

Prevention and treatment of allergic and vasomotor rhinitis.

Inhalation (spray).4 years-12 years - 50 μg (1 injection) into each nostril 1 time per day, if necessary up to 2 times a day. 12-18 years - in a dose of 100 mcg (2 injections) into each nostril 1 time per day (in the morning), if necessary up to 2 times a day; after reaching the control of the disease - 50 mcg (1 injection) into each nostril once a day.

Side effects:

Candidiasis of the oral cavity (dose-dependent effect) and throat, nasal congestion, rhinitis, pharyngitis, throat irritation, pain in the paranasal sinuses, sinusitis, influenza, upper respiratory tract infections, bronchitis, dysophagia (dosedependence), cough, weakness, malaise, headache pain, fever, insomnia, diarrhea.

Eye irritation, conjunctivitis, nasal bleeding, otitis media, tonsillitis, sneezing, dyspnea, pain or discomfort in the stomach, gastroenteritis, colitis, nausea and / or vomiting, pelvic inflammatory disease, vaginal candidiasis, vaginitis, vulvovaginitis, dysmenorrhea, dizziness, migraine , pain in the joints, soreness, stretching, muscle tension, dermatitis, rash.

Itenko-Cushing's syndrome, increased intraocular pressure, glaucoma (increased risk of glaucoma or increased intraocular pressure with prolonged therapy with high doses),cataract (increased risk of development of posterior subcapsular cataract with prolonged treatment with high doses), weight gain, anxiety, agitation, depression, ecchymosis, pruritus, systemic eosinophilic vasculitis, paradoxical or bronchospasm-induced hypersensitivity reactions, allergic reactions (suppression of adrenal function in doses more than 750 mcg per day, however, the sensitivity in individuals varies significantly), osteoporosis (more than 750 mg per day - a significant decrease in bone mineral density ani), growth retardation in children (200 μg per day - slowing the growth rate by 0.43 cm per year).

Intranasal administration.

Dryness, burning or other signs of irritation of the nasal mucosa, nosebleeds, pharyngitis, cough, asthma symptoms, headache, nausea / vomiting.

Rhinorrhea, flu-like symptoms, fever, bronchitis, dizziness, abdominal pain, diarrhea. Candidiasis of the mouth and pharynx.

External application.

Folliculitis, furunculosis, pustulosis, pyoderma, vesicular rashes, vesicles or bulls with hemorrhagic contents (purpura), telangiectasia, thinning of the epidermal layer, skin atrophy,hyperesthesia, numbness of fingers, attachment of secondary infection, dryness, irritation, peeling, burning, reddening of the skin, transient rash, allergic contact dermatitis, itching.

With prolonged use or other factors that increase absorption: changes in pigmentation, ruptures, skin maceration, atrophy of subcutaneous tissue, hair loss, burning, acne, ecchymosis, hypertrichosis, hypertension, stomach ulcers, secondary glaucoma, cataracts, hypokalemic syndrome, Cushing's syndrome, muscle weakness, perioral dermatitis, increased pressure, rapid weight gain, swelling of the lower limbs.

Overdose:

Symptoms: Nausea, vomiting, sleep disorders, euphoria, agitation, depression. With prolonged use in high doses - osteoporosis, fluid retention in the body, increased blood pressure and other signs of hypercorticism, including Itenko-Cushing syndrome, secondary adrenal insufficiency.

Treatment: against the background of the gradual withdrawal of the drug maintenance of vital functions, electrolyte balance correction, antacids, phenothiazines, Li + preparations; with the syndrome of Itenko-Cushing - aminoglutethimide.

Interaction:

Due to the very low concentrations of fluticasone propionate in plasma after application of the nasal spray, clinically significant interactions are unlikely.

Ritonavir (a highly active inhibitor of coenzyme CYP3A4 of the cytochrome P450 enzyme system) can significantly increase plasma concentrations of fluticasone propionate, resulting in a dramatic decrease in serum cortisol levels, systemic side effects, including Cushing's syndrome and suppression of adrenal function.

Inhibitors of the isoenzyme CYP3A4 of the cytochrome P450 enzyme system cause negligible (erythromycin) or insignificant (ketoconazole) an increase in the concentrations of fluticasone propionate in plasma, which does not entail any noticeable decrease in serum cortisol concentrations. Nevertheless, caution should be exercised when combining inhibitors of the CYP3A4 isoenzyme enzyme system of cytochrome P450 (for example, ketoconazole) and fluticasone propionate because of a possible increase in the plasma concentration of the latter. Post-registration observation reported cases of systemic effects of corticosteroids,such as Cushing's syndrome and suppression of adrenal function, with the combined use of fluticasone propionate and ritonavir. Therefore, simultaneous use of ritonavir and fluticasone propionate should be avoided, unless the potential benefit to the patient exceeds the possible risk of developing systemic side effects of corticosteroids.

Special instructions:

Use minimally effective doses to minimize systemic effects. With increasing doses, the bronchi's ability to relax is increased.

Rinsing of the mouth and throat after each inhalation - prevention of oral candidiasis, hoarseness and throat irritation. Do not swallow water after rinsing.

The use of a spacer reduces the likelihood of developing candidiasis, dysphonia, increases drug delivery to the lower respiratory tract and local activity of glucocorticoids.

Synthetic fluorinated glucocorticoid for inhalation. Apply inhalation, intranasal and externally.

A small dose-dependent effect is established. Most individuals (children and adults with mild and moderate asthma) do not achieve clinically significant improvement when treated at a dose of 500 mcg per day or more compared to doses of 200 mcg per day or less.In patients with severe steroid-dependent asthma, when dosing or lowering the dose of systemic glucocorticoids, doses of 2000 μg per day are more effective than 1000-1500 μg per day.

Impact on the ability to drive vehicles and manage mechanisms.

Data on the effect of the drug on the ability to drive vehicles are not obtained, but side effects that the drug may cause should be considered.

Instructions

Fluticasone (Fluticasonum)