Budesonide-intel
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Budesonide-INTELI (BUDESONID-INTELI)
Composition:
Active substance: budesonid;
One dose contains 50 mcg or 200 mcg of micronized budesonide;
Excipients: oleic acid, anhydrous ethanol, 1,1,1,2-tetrafluoroethane (HFA-134a).
Pharmaceutical form. Pressurized inhalation, suspension.
Main physicochemical properties:
At release: for the 50 mcg/dose dosage: white suspension;
for the 200 mcg/dose dosage: white suspension with typical odor and taste.
During shelf life: for both dosages: white suspension.
Pharmacotherapeutic group.
Inhaled drugs used in the treatment of obstructive respiratory diseases. Glucocorticoids. ATC code R03BA02.
Pharmacological properties.
Pharmacodynamics. Budesonide is an active synthetic glucocorticoid used for the treatment of allergic and inflammatory diseases of the respiratory tract. It exhibits minimal mineralocorticosteroid activity. It belongs to prolonged-action drugs suitable for once-daily dosing. Budesonide is characterized by local anti-inflammatory action due to its high lipophilicity and ability to penetrate intracellularly and bind to glucocorticoid receptors. The mechanism of action of budesonide involves the formation of complexes with cytoplasmic glucocorticoid receptors. Hormone-receptor complexes penetrate into the nuclei of target cells (eosinophils, neutrophils, lymphocytes), bind to DNA, and activate genes responsible for lipocortin production. Lipocortin is an inhibitor of phospholipase A2 – an enzyme that suppresses the synthesis of inflammatory mediators: histamine, leukotrienes, and cytokines.
In respiratory tract tissues, budesonide forms conjugates with fatty acid esters, which accumulate within cells. When the concentration of budesonide within cells decreases, fatty acid steroid esters are broken down under the influence of lipase. The released budesonide can form hormone-receptor complexes, which mediate the development of the drug's anti-inflammatory effect. The ability of budesonide to form conjugates with fatty acids explains the mechanism of its delayed-type local anti-inflammatory activity and the high level of therapeutic efficacy.
The drug has a higher affinity for glucocorticoid receptors in bronchial tissue compared to beclomethasone dipropionate, thus demonstrating greater local anti-inflammatory and anti-allergic activity. Significant improvement in pulmonary function parameters is observed within several days (7–10 days) after initiation of treatment. Budesonide does not affect bronchial smooth muscle. The drug reduces bronchial hyperresponsiveness, suppresses the early phase of allergic reaction (after sufficiently prolonged use) and the late phase, thereby preventing asthma attacks. Budesonide also reduces bronchospasm induced by physical exertion, cold air, or sulfur dioxide.
Pharmacokinetics. The drug is rapidly absorbed after inhalation. Approximately 34% of the administered dose deposits in the lungs. Absolute systemic bioavailability amounts to 39% of the administered dose. Maximum plasma concentrations of budesonide are reached within 30 minutes after inhalation. The volume of distribution is approximately 2–3 L/kg. Metabolism of the majority of budesonide (approximately 90%) occurs in the liver via the enzyme CYP3A4, resulting in metabolites with low glucocorticosteroid activity. The glucocorticosteroid activity of the main metabolites, 6-beta-hydroxybudesonide and 16-alpha-hydroxybudesonide, is less than 1% compared to the active substance. Approximately 90% of the administered dose is inactivated during the first pass through the liver. Pulmonary metabolism is negligible. In adults, the plasma half-life of the drug averages 2 hours; in children, it is 1.5 hours. Plasma protein binding of budesonide ranges from 85% to 90%. The drug is excreted via urine (70%) and bile. Since the primary action of budesonide occurs in the respiratory tract, there are no data establishing a correlation between plasma concentration of the drug and its therapeutic efficacy.
Clinical characteristics.
Indications.
Bronchial asthma.
Contraindications.
Hypersensitivity to any of the components of the drug.
Interaction with other medicinal products and other forms of interaction.
Budesonide metabolism is primarily mediated by CYP3A4; therefore, inhibitors of this enzyme, such as ketoconazole and itraconazole, may increase systemic exposure to budesonide (see sections "Special precautions for use" and "Pharmacological properties"). Due to lack of dosing data, concomitant use of these drugs should be avoided. If concomitant use is unavoidable, the interval between administration of these medicinal products should be as long as possible. A reduction in the dose of budesonide should also be considered. Other potent CYP3A4 inhibitors may likewise lead to a significant increase in plasma budesonide levels.
Limited data on similar interactions with high doses of inhaled budesonide show that concomitant administration of itraconazole 200 mg once daily with inhaled budesonide (single dose of 1000 µg) leads to a significant increase in plasma concentration of the substance (on average, fourfold).
In women concurrently taking estrogens or hormonal contraceptives, plasma concentrations of budesonide were increased and corticosteroid effects were enhanced; however, when budesonide was used together with low-dose combined oral contraceptives, this effect was not observed.
Cimetidine has a weak inhibitory effect on the hepatic metabolism of budesonide, but this phenomenon is not clinically significant.
Due to possible suppression of adrenal gland function, an ACTH (adrenocorticotropic hormone) stimulation test for diagnosing pituitary insufficiency may yield false results (low values).
Children
Interaction studies have been conducted only in adults.
Special precautions for use.
The drug should be used with caution in patients with active or inactive pulmonary tuberculosis and fungal or viral respiratory tract infections.
Patients without steroid dependence. Therapeutic effect is usually achieved within 10 days. In patients with excessive mucus production in the bronchi, a short-term (approximately 2 weeks) additional course of oral corticosteroids may be initially administered. After completion of oral corticosteroid therapy, treatment with budesonide as monotherapy may be sufficient.
Patients with steroid dependence. Transition from oral corticosteroids to budesonide may begin when the patient is in a relatively stable phase of the disease. In such cases, budesonide should be used in combination with the previously administered dose of oral corticosteroid for approximately 10 days.
After this period, the dose of oral corticosteroids should be gradually reduced (e.g., by 2.5 mg of prednisolone or equivalent per month) until the lowest possible dose is reached. In many cases, complete replacement of oral corticosteroids with budesonide is possible.
During transition from oral corticosteroid therapy to budesonide, a reduction in systemic corticosteroid effects is usually observed, which may lead to the appearance of allergy or arthritis symptoms such as rhinitis, eczema, and musculoskeletal pain. Specific treatment should be prescribed for these conditions. In rare cases, symptoms such as fatigue, headache, nausea, and vomiting may occur, indicating systemic glucocorticoid insufficiency. In such cases, temporary dose increase of oral corticosteroid may sometimes be required.
As with other forms of inhaled therapy, paradoxical bronchospasm may occur immediately after dosing. If severe reactions occur, treatment should be re-evaluated and, if necessary, alternative therapy initiated.
In patients who have required high-dose systemic corticosteroid therapy or prolonged treatment with inhaled corticosteroids at the highest recommended dose, there is also a risk of adrenal suppression. In such patients, symptoms of adrenal insufficiency may occur during periods of severe stress. Additional systemic corticosteroid therapy may be considered during stressful situations or prior to planned surgical procedures.
Systemic effects may occur with any inhaled corticosteroid, especially when high doses are used over prolonged periods. The likelihood of such effects is significantly lower with inhaled corticosteroids than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children, decreased bone mineral density, cataracts, and glaucoma. Rarely, psychological and behavioral disorders may occur, including psychomotor hyperactivity, sleep disturbances, anxiety, depression, or aggression (particularly in children). Therefore, the dose of inhaled corticosteroids should be titrated to the lowest effective dose that maintains adequate control of bronchial asthma.
Budesonide is not intended for rapid relief of acute episodes of bronchial asthma requiring short-acting inhaled bronchodilators. If treatment with short-acting bronchodilators is ineffective or if the patient requires more frequent inhalations than usual, medical intervention is necessary. In such cases, intensification of standard therapy should be considered, for example, by increasing the dose of inhaled budesonide, adding a long-acting beta-agonist, or initiating a course of oral glucocorticosteroids.
Impaired liver function may affect the elimination of glucocorticosteroids from the body, as reduced clearance leads to increased systemic exposure. The potential for adverse effects should be considered.
Patients receiving high-dose systemic corticosteroid therapy or prolonged treatment with the maximum recommended dose of inhaled corticosteroids may have an increased risk of adrenal suppression. In such patients, signs and symptoms of adrenal insufficiency may occur during periods of severe stress. The need for additional systemic corticosteroid therapy during stressful periods or prior to surgery should be considered. These patients should be instructed to carry a card stating that they may require steroid supplementation. Treatment with additional systemic steroids or the medicinal product Budesonide-Intel should not be discontinued abruptly.
However, plasma clearance after intravenous administration of budesonide was found to be similar in patients with liver cirrhosis and healthy volunteers. After oral administration, systemic bioavailability of budesonide increased due to impaired liver function, resulting from reduced presystemic metabolism. The clinical significance of these changes for budesonide treatment has not been fully established, as data on the inhaled formulation are lacking; however, increased plasma levels and, consequently, an increased risk of systemic adverse reactions may be expected.
It has been shown that oral administration of ketoconazole and itraconazole (known inhibitors of CYP3A4 activity in the liver and intestinal mucosa) increases systemic exposure to budesonide. Concomitant use of ketoconazole, itraconazole, HIV protease inhibitors, or other potent CYP3A4 inhibitors should be avoided. If concomitant use cannot be avoided, the interval between administration of these drugs should be as long as possible. A reduction in the dose of budesonide should also be considered (see section "Interaction with other medicinal products and other forms of interaction").
Oral candidiasis may develop during treatment with inhaled corticosteroids. This infection may require appropriate antifungal treatment, and in some patients, discontinuation of therapy may be necessary (see also section "Method of administration and dosage").
Patients using inhaled corticosteroids should rinse their mouth with water after each dose to reduce the risk of fungal infection of the oropharynx.
Warning: administration of budesonide to athletes may result in a positive doping test.
Children
Effect on growth
In children receiving long-term treatment with inhaled corticosteroids, regular monitoring of growth is recommended. If growth retardation occurs, therapy should be re-evaluated with the aim of reducing the inhaled corticosteroid dose to the lowest possible level that maintains effective control of bronchial asthma. The benefits of corticosteroid therapy should be carefully weighed against the potential risk of growth suppression. In addition, referral of the patient to a pediatric pulmonologist is important.
Use during pregnancy or breastfeeding.
Pregnancy
Use of budesonide during pregnancy requires careful assessment of benefit to the mother versus risk to the fetus. Inhaled glucocorticosteroids should be preferred over oral glucocorticosteroids due to their lower systemic effects when used at doses required to achieve equivalent respiratory effects.
Breastfeeding period
Budesonide passes into breast milk. However, no adverse effects on the breastfed infant are expected when budesonide is used at therapeutic doses. Budesonide may be used during breastfeeding.
Supportive treatment with inhaled budesonide (200 or 400 mcg twice daily) in breastfeeding women with bronchial asthma results in only minimal systemic exposure of budesonide in breastfed infants.
Considering available data on inhaled budesonide and the fact that budesonide exhibits linear pharmacokinetic properties within therapeutic dose ranges after nasal, inhaled, oral, or rectal administration, exposure to budesonide in breastfed infants is expected to be low when used at therapeutic doses.
Ability to influence reaction rate while driving or operating machinery.
Budesonide does not affect reaction speed while driving or operating machinery.
Method of Administration and Dosage
For inhalation use only.
Children aged 5 to 12 years: 200–800 mcg daily, divided into 2–4 doses.
Adults (including elderly patients) and children aged 12 years and older: 200–1600 mcg daily, divided into 2–4 doses.
After achieving the desired clinical effect, the maintenance dose should be gradually reduced to the lowest dose required to control symptoms.
After each inhalation, the patient should rinse the mouth with water.
Instructions for correct use:
Before using the aerosol, check the expiry date of the medication. If the inhaler is new or has not been used for several days, shake it well and release one dose into the air to ensure that it is working properly.
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- After inhaling, hold your breath to ensure maximum penetration of the medication.
- If necessary, continue for several seconds and repeat the procedure again (3, 4).
- Close with the cap after use.
The plastic adapter must be cleaned regularly. To clean, remove the metal container and rinse the adapter with warm (not hot) soapy water.
Rinse thoroughly, dry the adapter, and reassemble the device. After reassembly, close with the cap.
Children.
The medication is contraindicated in children under 5 years of age.
Overdose.
With prolonged use of high doses, systemic effects of glucocorticoids may occur, such as hypercorticism (edema, facial swelling) and suppression of the hypothalamic-pituitary-adrenal system. Electrolyte imbalance should be corrected by using potassium-sparing diuretics, such as spironolactone and triamterene.
Side effects.
The frequency of adverse reactions is presented below according to the following criteria: very common (≥1/10); common (from ≥1/100 to <1/10); uncommon (from ≥1/1,000 to <1/100); rare (from ≥1/10,000 to <1/1,000); very rare (<1/10,000).
Infections and infestations
Common: oropharyngeal candidiasis.
Rare: pneumonia (in patients with COPD (chronic obstructive pulmonary disease)).
Immune system disorders
Rare: immediate- and delayed-type hypersensitivity reactions (including rash, contact dermatitis, urticaria, angioedema, and anaphylactic reaction).
Endocrine system disorders
Rare: signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation*.
Psychiatric disorders
Rare: psychomotor hyperactivity, sleep disorders, aggression, irritability, psychosis.
behavioral changes (mainly in children).
Uncommon: anxiety, depression.
Nervous system disorders
Uncommon: tremor**.
Eye disorders
Uncommon: cataract.
Not known: glaucoma.
Respiratory, thoracic and mediastinal disorders
Common: cough, hoarseness, throat irritation.
Rare: dysphonia, bronchospasm, hoarseness***.
Skin and subcutaneous tissue disorders
Rare: bruising.
Musculoskeletal and connective tissue disorders
Not known: muscle spasms.
* see section "Children" below;
** based on frequency reported in clinical trials;
*** rarely in children.
Description of selected adverse reactions
Oropharyngeal candidiasis occurs due to deposition of the medicinal product in the oropharynx. Rinsing the mouth with water after each inhalation minimizes this risk.
As with any inhaled therapy, paradoxical bronchospasm may very rarely occur (see section "Special warnings and precautions for use").
There is an increased risk of pneumonia in patients with newly diagnosed COPD who initiate inhaled corticosteroid therapy. However, a weighted analysis of eight pooled clinical trials did not demonstrate an increased risk of pneumonia. Results from the first seven of these eight trials were published as a separate meta-analysis.
Systemic effects may occur with inhaled corticosteroids, particularly when high doses are used over prolonged periods. Such effects are considerably less likely with inhaled therapy than with oral corticosteroids. Possible systemic effects include decreased bone mineral density. The effect is likely dose- and exposure duration-dependent, and may also be influenced by concomitant and prior corticosteroid therapy, as well as individual sensitivity.
Children
Due to the risk of growth retardation in children, growth monitoring should be performed in pediatric patients as described in the section "Special warnings and precautions for use".
Shelf life. 2 years.
Storage conditions.
Store at temperatures not exceeding 30 °C.
Keep out of the reach of children.
Pressurized container – do not pierce. Do not throw into fire, even when empty.
Protect from direct sunlight. Do not store near sources of heat.
Do not freeze.
Packaging.
Aluminum canister containing 200 doses (10 ml) of 50 mcg/dose or 200 mcg/dose of budesonide, with a plastic actuator and cap, in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
LABORATORIO ALDO-UNION, S.L. / LABORATORIO ALDO-UNION, S.L.
Manufacturer's address.
Baronesa de Malda, 73, 08950 Esplugues de Llobregat, Barcelona, Spain / Baronesa de Malda, 73, 08950 Esplugues de Llobregat, Barсelona, Spain.
Marketing Authorization Holder.
JSC «INTELI GENERICS NORD» / JSC «INTELI GENERICS NORD».
Address of Marketing Authorization Holder.
Seimyniskiu 3, 09312, Vilnius, Lithuania / Seimyniskiu 3, 09312, Vilnius, Lithuania.