Budesonide - instructions for use, doses, side effects, contraindications

Interaction with intracellular glucocorticoid receptors - formation of dimers of the complex "glucocorticoid - glucocorticoid receptor".Penetration of the activated receptor into the nucleus, binding to glucocorticoid-sensitive regulatory elements deoxyribonucleic acid - a specific effect on gene expression (activation and inhibition) that encode anti-inflammatory and pro-inflammatory factors.

Budesonide has a pronounced local anti-inflammatory effect and a weak systemic effect.

The anti-inflammatory effect of budesonide is due to several factors.

1. The drug induces the synthesis of lipocortin, inhibiting the activity of phospholipase A2. Inhibition of phospholipase A mediated2 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 genes of cyclooxygenase of the second type,which also leads to a decrease in the synthesis of prostaglandins in the inflammatory focus, including pro-inflammatory prostaglandins E2 and I2.

3. Budesonide 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 glucocorticoid, 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. The decrease in the number of circulating lymphocytes (T and B cells), monocytes, eosinophils and basophils due to their movement from the vascular bed to the lymphoid tissue is determined. In this case, the function of leukocytes and especially tissue macrophages is suppressed, which limits their ability to react to antigens, mitogens, pathogenic microorganisms, and also to produce kinins and pyrogenic factors.

This effect of budesonide leads to the restoration of respiratory function and reduced hyperreactivity of the bronchi.

Increases the number of active beta-adrenergic receptors,restores the body's response to beta-adrenergic bronchodilators after long-term use.

In standard studies in vitro the animal models show that the affinity of budesonide to specific receptors of glucocorticoids exceeds that of cortisol by 200 times, and the local anti-inflammatory effect of budesonide is 1000 times higher than that of cortisol. When studying the systemic activity of budesonide in animal experiments, it was shown that with subcutaneous administration the effect of budesonide was 40 times stronger than that of cortisol, and 25 times with oral administration.

Pharmacokinetics:

Quickly absorbed from the lungs and the gastrointestinal tract. With intranasal administration, very little is absorbed from the mucous membrane of the nasal cavity (only 20% enters the systemic circulation). After inhalation, approximately 25% of the dose falls into the alveoli. Caught in gastrointestinal tract the part almost completely (90%) is destroyed (inactive metabolites are formed) at the "first passage" through the liver. Bioavailability is 10% of the amount entered in the stomach, 25-30% of the budesonide that enters the alveoli is absorbed. Maximum concentration in the blood is reached 15-45 minutes after inhalation and intranasal administration. Binding to plasma proteins is 88%. Has a high system clearance (84 liters per hour). Half-life from the plasma - 2.8 hours. It is excreted in the urine, in part - with bile in the form of metabolites.

The maximum concentration in the blood plasma is reached approximately 30 minutes after inhalation. Systemic bioavailability with oral administration is 10%. Binding to proteins is 85%. About 90% of absorbed budesonide is metabolized by the "first pass" through the liver with the participation of microsomal enzymes (predominantly CYP3A4) to two major metabolites - 6-beta-hydroxy-budesonide and 16-alpha hydroxyprednisolone (the glucocorticoid activity of metabolites is less than 1/100 of budesonide activity , of the rest, about 90% binds to albumin and is in an inactive state.

Indications:

Inhalation: bronchial asthma as a basic therapy with insufficient effectiveness of bronchodilators, cromoglycic acid and ketotifen, as well as to reduce the dose of systemic glucocorticoids; xobstructive pulmonary disease.

Inside: Crohn's disease involving the ileum and / or ascending colon (to induce remission in mild and moderate forms); collagenous colitis.

Intranasally: withezonous and year-round allergic rhinitis; vasomotor rhinitis; prevention of nasal polyp growth after polypectomy, non-infectious inflammatory processes in the nasal cavity.

Outer: atopic dermatitis, psoriasis, eczema, red flat lichen.

ICD-10

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

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

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

X.J40-J47.J45 Asthma

X.J40-J47.J44 Other chronic obstructive pulmonary disease

XI.K50-K52.K50 Crohn's disease [regional enteritis]

Contraindications:

Hypersensitivity.

For inhalation forms: active form of pulmonary tuberculosis, fungal infections of the respiratory system; Children's age up to 3 months (suspension), up to 6 years (powder), up to 16 years (solution for inhalation).

For oral forms: infections gastrointestinal tract (bacterial, fungal, amoebic, viral), severe violations of liver function, children's age, breast-feeding.

For intranasal forms: fungal, bacterial and viral infections of the respiratory system, tuberculosis of the respiratory system, pregnancy, breast-feeding, age to 18 years.

For external use: hypersensitivity.

Carefully:

External: glaucoma, severe hepatic insufficiency, hypothyroidism, recently suffered myocardial infarction, bacterial, fungal, parasitic and viral infections (including amoebiasis, tuberculosis, herpes of the eyes).

When administered orally: tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma, cataract, a burdened family history of diabetes mellitus or glaucoma.

Pregnancy and lactation:

Recommendations Food and Drug Administration (US Food and Drug Administration) category C. A means of choice during pregnancy in the United States due to the large clinical experience of its use. Standard doses of inhaled glucocorticosteroids, as a rule, do not cause abnormalities on the part of the fetus. Adequate 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 incidence of cleft palate, placental insufficiency, spontaneous abortion and intrauterine growth retardation of the fetus. In newborns whose mothers received inhaled glucocorticosteroids 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. The question of use during breastfeeding should be addressed on the basis of a comparison of risk and benefit.

Dosing and Administration:

Apply inhalation, intranasal, inside and outside.

Inhalation powder adult, if the previous treatment of bronchial asthma was carried out only beta₂-adrenostimulants or inhaled glucocorticosteroids, in a dose of 200-800 mcg per day in 2-4 doses. If previously used systemic glucocorticoids - 400-800 mcg 2 times a day. The maximum dose for people who have previously received only beta₂agonists, 800 mcg per day, for people who received previously inhaled or systemic glucocorticoids, 1600 mcg per day.

Inhalation powder for children over 6 years of 200 mcg per day; the maximum dose is 400 micrograms per day in 2 divided doses. Suspension for inhalation - adults 1000-2000 mkg, children 3 months - 12 years 250-1000 mcg 2 times a day, if necessary, previously diluted with 2-4 ml of 0.9% sodium chloride solution.

Seasonal and all-the-year-round allergic rhinitis, vasomotor rhinitis (all-the-year-round non-allergic rhinitis, 400 mcg per day), prevention of nasal polyps after polypectomy (280 mcg per day for 8 weeks, 200 mcg 2 times a day), non-infectious inflammatory processes in the nasal cavity (intranasal to adults and children 6 years and older, 200 mcg in each nasal passage 1 time per day in the morning, total daily dose - 400 mcg). The maximum dose for children is 400 mcg per day, for adults - 800 mcg per day. When the effect is achieved, the dose is reduced.

Crohn's disease (light and medium-heavy forms involving the ileum and / or ascending colon). Use inside 3 mg 3 times a day for 30 minutes before meals, squeezed with enough liquid. The course of treatment is 8 weeks. The full effect usually comes in 2-4 weeks. Cancellation is carried out gradually.

Atopic dermatitis, psoriasis, eczema, red flat lichen: externally 1-2 times a day,with maintenance therapy - once a day. The course of treatment is 4 weeks.

Use in children

Bronchial asthma, standard doses. Inhalation. 1 month - 2 years: 50-100 mcg 2 times a day. 2 years - 12 years: 100-200 micrograms twice a day. 12-18 years: 100-400 micrograms twice a day.

Bronchial asthma, high doses. Inhalation. 1 month - 2 years: up to 200 mcg 2 times a day. 2 years - 12 years: up to 400 mcg 2 times a day. 12-18 years: 400-1000 micrograms twice a day.

Bronchopulmonary dysplasia. Inhalation (aerosol). Newborns: 400 mcg twice a day. 1-4 months: 400 mcg twice a day.

Bronchopulmonary dysplasia with independent breathing. Inhalation (nebulizer). Newborns: 500 mcg twice a day. 1-4 months: 500 mcg twice a day; in severe cases with a mass of 2.5 kg and more - 1 mg 2 times a day.

When inhaling aerosols, use a medium-sized spacer attached to the endotracheal tube; pumping air using the Ambu bag. Perform 10 air injections between the periods of activation of the inhaler.

Croup. Inhalation (nebulizer). 1 month - 18 years: in a dose of 2 mg once or split the dose into 2 parts with an interval of 30 minutes, if necessary, repeat after 12 hours.

Prevention and treatment of allergic and vasomotor rhinitis. Inhalation (spray).12-18 years: 2 injections (100 micrograms) into each nostril 1 time per day (in the morning) or 1 injection (50 micrograms) into each nostril 2 times a day. At achievement of the control over disease - on 1 injection in each nostril 1 time a day.

Polyposis of the nose. Inhalation (spray). 12-18 years: 1 injection (50 mcg) in each nostril 2 times a day for 3 months.

Crohn's disease of mild and moderate severity, affecting the ileum and ascending colon; collagenous colitis. Inside. 12-18 years: 3 mg 3 times a day for 8 weeks, reduce the dose within the last two weeks of admission.

Side effects:

For inhalation use: dryness or irritation in the oral cavity, dryness or irritation of the throat, flu-like symptoms, pharyngitis, laryngitis, dysphonia (dose-dependent effect), cough, headache. Oropharyngeal candidiasis, bruising (high dose), fatigue, weakness, malaise, insomnia, dizziness, weight gain, abdominal pain, nausea or vomiting, constipation or diarrhea, chest pain, palpitation, tachycardia, arrhythmia, cystitis, allergic reactions, swelling of the face, fingers, ankles, feet, lower limbs, unpleasant taste sensations.Esophageal candidiasis, gastroenteritis, slowing of growth rate in children, osteoporosis (more than 1500 micrograms per day - significant decrease in bone mineral density), cataract (increased risk of development of posterior subcapsular cataract with prolonged treatment with high doses), hypertension, hypercortisy, hyperglycemia, menstrual irregularities , fever, mental disorders (anxiety, aggressive reactions, depression, psychosis), rectal bleeding, nosebleeds, hemorrhagic rash and thinning of the skin (400-2000 micrograms per day), fainting , adrenal insufficiency (suppression of adrenal function in therapy at a dose of more than 1500 micrograms per day, but the sensitivity in patients varies significantly), pneumonia, bronchospasm, allergic reactions, decreased sense of smell and taste, increased risk of glaucoma or increased intraocular pressure in long-term treatment with high doses, oppression of the hypothalamic-pituitary-adrenal system (minimal at a dose of more than 1500 μg per day (400 μg per day in children)).

With intranasal application: mild and transient burning, dryness or other irritation in the nasal cavity and pharynx, sneezing attacks, headache.

Formation of scabs in the nasal cavity, epistaxis, persisting rhinorrhea and nasal congestion, lacrimation, sore throat, hoarseness, coughing, lethargy, dizziness, nausea or vomiting, pain in the stomach, loss of taste or smell. Candidiasis of the nasal cavity and pharynx, atrophic rhinitis, ulceration of the nasal mucosa, perforation of the nasal septum, conjunctivitis, increased intraocular pressure, glaucoma, cataracts, muscle pains, shortness of breath, allergic reactions, tinnitus.

When administered orally: the frequency of development and severity of side effects depend on the duration of the application, the amount of the dose used and the possibility of observing the circadian rhythm of the appointment.

On the part of the endocrine system: decreased tolerance to glucose, steroid diabetes mellitus or manifestation of latent diabetes mellitus, suppression of adrenal function, Itenko-Cushing syndrome (lunar face, obesity of the pituitary type, hirsutism, increased blood pressure, dysmenorrhea, amenorrhea, myasthenia, striae ), delay in sexual development in children.

From the side of the digestive system: nausea, vomiting, pancreatitis,"steroid" ulcer of the stomach and duodenum, erosive esophagitis, bleeding and perforation of the gastrointestinal tract, increase or decrease in appetite, flatulence, hiccough. In rare cases - increased activity of "liver" transaminases and alkaline phosphatase.

From the cardiovascular system: arrhythmias, bradycardia (up to cardiac arrest); development (in predisposed individuals) or increased severity of chronic heart failure, changes in the electrocardiogram, characteristic of hypokalemia, increased blood pressure, hypercoagulation, thrombosis. In patients with acute and subacute myocardial infarction - the spread of the focus of necrosis, slowing the formation of scar tissue, which can lead to rupture of the heart muscle.

From the nervous system: delirium, disorientation, euphoria, hallucinations, manic-depressive psychosis, depression, paranoia, increased intracranial pressure, nervousness or anxiety, insomnia, dizziness, vertigo, pseudotumor, cerebral palsy, headache, convulsions.

From the sense organs: the posterior subcapsular cataract,increased intraocular pressure with possible damage to the optic nerve, a tendency to develop secondary bacterial, fungal or viral infections of the eyes, trophic changes in the cornea, exophthalmos.

From the side of metabolism: increased excretion of Ca2+, hypocalcemia, weight gain, negative nitrogen balance (increased protein breakdown), increased sweating.

Caused by mineralocorticoid activity: fluid retention and Na+ (peripheral edema), hypernatremia, hypokalemic syndrome (hypokalemia, arrhythmia, myalgia or muscle spasm, unusual weakness and fatigue).

On the part of the musculoskeletal system: slowing growth and ossification processes in children (premature closure of the epiphyseal growth zones), osteoporosis (very rarely - pathological bone fractures, aseptic necrosis of the head of the humerus and thigh bone), rupture of the tendons of muscles, steroid myopathy, (atrophy).

On the part of the skin and mucous membranes: delayed healing of wounds, petechiae, ecchymosis, thinning of the skin, hyper- or hypopigmentation, steroid acne, striae, propensity to develop pyoderma and candidiasis.

Allergic reactions: generalized (skin rash, itching, anaphylactic shock), local allergic reactions.

Other: development or exacerbation of infections (the appearance of this side effect is promoted by jointly used immunosuppressants and vaccination), leukocyturia, withdrawal syndrome.

With intravenous administration: arrhythmias, hot flashes, convulsions. Locally - burning, numbness, pain, paresthesia at the injection site, infection at the injection site, rarely - necrosis of surrounding tissues, scar formation at the injection site; atrophy of the skin and subcutaneous tissue with intramuscular injection (especially dangerous is the introduction to the deltoid muscle).

With parenteral administration in the region of the head, neck, nasal concha, and scalp, it is possible to deposit crystals of the drug, in the vessels of the eye - a sudden loss of vision.

When intracranial introduction - nasal bleeding (during neurosurgical operations).

With external application: steroid acne, purpura, telangiectasia, burning and itching of the skin, irritation and dry skin. With long-term use and / or when applied to large surfaces, systemic side effects are possible.

Overdose:

When ingestion: 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 a gradual discontinuation of the drug maintenance of vital functions, correction of electrolyte balance, antacids, phenothiazines, drugs Li+; with the syndrome of Itenko-Cushing - aminoglutethimide.

Acute overdose with inhalation is practically impossible due to the presence of a special mechanism in the dosing system, which prevents the intake of an excessive dose of the drug in the body. There are no special clinical manifestations of acute overdose, no special treatment is required.

Interaction:

Alcohol, non-steroidal anti-inflammatory drugs - increased risk of bleeding (including hemorrhagic stroke) and ulceration of the gastric mucosa.

Aminoglutethimide - suppression of adrenal function (additional administration is required glucocorticosteroids).

Amphotericin B (parenterally), inhibitors of carbonic anhydrase - the risk of severe hypokalemia.

Antiglaucoma means - correction of the dose due to glaucocorticosteroids.

Anticholinergics, especially atropine, - risk of intraocular hypertension.

Acetazolamide - the risk of hypernatremia, edema, hypocalcemia (osteoporosis).

Anabolic steroids, androgens - the risk of edema, severe acne.

Antidepressants tricyclics - aggravation of steroid-dependent disorders of the psyche. Do not apply!

Anticoagulants indirect (coumarin and indanedione derivatives), anticoagulants direct, thrombolytics - risk of hemorrhagic stroke.

Antithyroid drugs, thyroid hormones - correction of the dose of glucocorticosteroids due to reduced clearance in hypothyroidism and increased - in the hyperthyroid state.

Asparaginase - increasing its toxic effects.

Vaccines, live viruses or other immunization - pharmacological (immunosuppressive) doses of glucocorticosteroids lead to stimulation of replication of live viruses, an increased risk of developing viral diseases, a decrease in the formation of antibodies to the vaccine.

Diuretics - reduction of their natriuretic and diuretic effects, hypokalemia.

Inhibitors of acetylcholinesterase - a risk of severe weakness in myasthenia gravis (cancellation 24 hours before the start of glucocorticosteroid therapy).

Isoniazid, mexiletine - Increase in clearance of isoniazid, mexiletine, decrease in plasma concentration (dose adjustment).

Immunosuppressants, others - the risk of infection.

Carbamazepine, ephedrine, phenobarbital, phenytoin, rifampicin - increase of clearance glucocorticosteroids.

Ketoconazole - reduced clearance glucocorticosteroids (increased risk of side effects).

Contact lenses - increased risk of infection.

Macrolides - reduced clearance of glucocorticosteroids.

Mitotan - an increase in the dose of glucocorticosteroids.

Nondepolarizing muscle relaxants - the risk of respiratory depression (due to hypokalemia, induced by glucocorticosteroids).

Oral antidiabetic agents and insulin - dose adjustment of one or both drugs in combination. Correction of an antidiabetic remedy after cessation of glucocorticoid therapy.

Cardiac glycosides - the risk of their overdose and arrhythmia due to hypokalemia.

Somatotropin - depression of the growth stimulating response to somatotropin (prednisolone in a daily dose of less than 2.5-3.75 mg / m²(by mouth) and 1.25-1.88 mg / m2 body surface (parenteral).

Means or products that contain large amounts of sodium - the risk of edema and hypertension.

Means that induce liver enzymes, an increase in the clearance of glucocorticosteroids.

The drugs that stimulate the activity of liver enzymes are a decrease in the effects of glucocorticosteroids by increasing their metabolism.

Folic acid - increased demand for folate with long-term therapy with glucocorticosteroids.

Estrogen-containing oral contraceptives - increased clearance and reduced half-life of glucocorticosteroids (dose adjustment).

Metabolism budesonide occurs with the participation of cytochrome P450-3A, therefore, joint use of ketoconazole, cyclosporine, ethinylestradiol and toleandromycin should be avoided because of the possible increase in plasma concentrations of budesonide.

Special instructions:

Use minimally effective doses to prevent systemic effects.

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 the glucocorticoid. Budesonide can not be used with a spacer. Use bronchodilators a few minutes before the glucocorticoid to increase its penetration into the respiratory tract. The onset of constant therapy with moderate and low doses of inhaled glucocorticoids in bronchial asthma is just as effective as the initiation of treatment with high doses followed by a decrease.

High doses of inhaled glucocorticoids in bronchial asthma of mild to moderate severity almost do not improve disease control compared to low / moderate doses, but increase the risk of side effects. The addition of a drug from another group is preferred before the increase in the doses of inhaled glucocorticoids.

It is necessary to monitor the functions of the adrenal glands (concentration adrenocorticotropic hormone (corticotropin) in blood, cortisol of blood or urine, 17-glucocorticoids and 17-ketosteroids in urine), to evaluate growth and development in children,control of inhalation technique, lung function, blood pressure level, conduct bone densitometry, early diagnosis of infectious diseases, monitor the concentration of serum electrolytes, blood or urine glucose, conduct occult blood feces analysis, ophthalmological examination for treatment for more than 6 weeks (cataract risk, glaucoma , infectious diseases), tonometry.

There is insufficient information on the effectiveness of intranasal glucocorticosteroids with intermittent and persistent allergic rhinitis in children.

Inhalation glucocorticosteroids in a dose of 400 mcg per day (according to beclomethasone) are superior in effectiveness to antileukotriene agents, sodium cromoglicate in the treatment of asthma in both adults and children. Glucocorticosteroid - first-line therapy in people with persistent asthma.

In persons with mild or moderate persistent asthma who have not received inhalation glucocorticosteroids, combined therapy with inhalation glucocorticosteroids and beta₂-adrenomimetics long-acting has no advantages over monotherapy with inhalation glucocorticosteroids.

There is no evidence of the superiority of inhalation glucocorticosteroids through the nebulizer compared with standard inhalers.

Reduce the frequency of exacerbations of chronic obstructive pulmonary disease. Slowing pulmonary function impairment in persons with chronic obstructive pulmonary disease after taking at least 2 years (dose-dependent efficacy), but does not affect it in the long term.

Intranasal glucocorticoids are more effective than antihistamines for oral administration in the treatment of allergic rhinitis.

Intranasal glucocorticoids in combination with antibiotics improve the course of acute otitis media and reduce the risk of associated deafness. Intranasal glucocorticoids are superior to H₁-local blockers for the treatment of allergic rhinitis.

With Crohn's disease budesonide is less effective than conventional glucocorticoids, however, when it is used, the risk of side effects is much lower. Budesonide at a dose of 6 mg per day is ineffective in preventing relapses after therapeutically or surgically achieved remission.

Not effective for the prevention of wheezing with bronchiolitis.

When pulmonary tuberculosis is prescribed only in combination with anti-tuberculosis drugs.

If the patient has infectious diseases of the respiratory tract (including fungal), the drug must be combined with the use of appropriate specific therapy.

If the patient develops paradoxical bronchospasm after inhalation of the drug, inhalation should be prescribed beta₂-adrenomimetics before each use of the drug.

The abolition of therapy with the drug should be gradual.

For children and adolescents receiving treatment with the drug (regardless of the method of delivery) for an extended period, it is recommended that growth rates be regularly monitored.

Impact on the ability to drive vehicles and manage mechanisms

Budesonide does not affect the ability to engage in potentially hazardous activities requiring increased attention and high speed of psychomotor reactions.

Instructions

Budesonide (Budesonidum)