Budesonide-intel neb suspension for nebulization 0.5 mg/ml container 2 ml No. 20

Instructions Budesonide-intel neb suspension for nebulization 0.5 mg/ml container 2 ml No. 20

Composition

active ingredient: budesonide; 0.5 mg/ml;

1 single-dose container contains 1 mg of budesonide;

Excipients: sodium chloride, sodium citrate, disodium edetate, polysorbate 80, anhydrous citric acid, water for injections.

Dosage form

Suspension for spraying.

Main physicochemical properties: white homogeneous suspension.

Pharmacotherapeutic group

Drugs used in obstructive airway diseases. ATX code R03B A02.

Pharmacological properties

Pharmacodynamics

Budesonide is a glucocorticosteroid with a strong local anti-inflammatory effect, the frequency and severity of side effects of which are lower than those of oral corticosteroids.

Local anti-inflammatory effect

The exact mechanism of action of glucocorticosteroids in the treatment of bronchial asthma is not fully understood. Anti-inflammatory effects, such as inhibition of the release of inflammatory mediators and suppression of cytokine-mediated immune responses, are likely to play an important role.

A clinical trial in patients with bronchial asthma, comparing inhaled and oral budesonide dosage forms at doses calculated to achieve similar systemic bioavailability, showed a statistically significant superiority of the efficacy of inhaled budesonide over oral budesonide compared to placebo. Thus, the therapeutic effect of standard doses of inhaled budesonide can be largely explained by a direct action on the respiratory tract.

In a provocation study, pretreatment with budesonide for 4 weeks resulted in a reduction in bronchoconstriction in both immediate and delayed asthmatic reactions.

Start of effect

After a single inhalation of budesonide orally using a dry powder inhaler, improvements in lung function are achieved within a few hours. It has been shown that after therapeutic use of budesonide orally inhaled using a dry powder inhaler, improvements in lung function occur within 2 days of starting treatment, although the maximum effect may not be achieved for up to 4 weeks.

Airway reactivity

It has also been shown that in patients with hyperresponsiveness, budesonide reduces airway reactivity to histamine and methacholine.

Exercise-induced bronchial asthma

Inhaled budesonide therapy has been used effectively to prevent exercise-induced asthma attacks.

Growth

Limited data from long-term studies suggest that most children and adolescents treated with inhaled budesonide eventually reach their adult height. However, a small initial, albeit transient, growth retardation (approximately 1 cm) has been observed. In most cases, this occurs within the first year of treatment (see section 4.4).

Effect on plasma cortisol concentration

In studies in healthy volunteers, budesonide administered by dry powder inhaler had a dose-dependent effect on plasma and urinary cortisol levels. At recommended doses, budesonide dry powder inhaler has significantly less effect on adrenal function than prednisone 10 mg, as confirmed by ACTH (adrenocorticotropic hormone) assays.

Children

Clinical application: bronchial asthma

The effectiveness of budesonide has been studied in a large number of studies that have demonstrated the effectiveness of the drug in adults and children when used once or twice daily for the prophylactic treatment of persistent bronchial asthma.

Clinical application: croup

Several studies have compared budesonide with placebo in children with croup. Representative examples of studies of budesonide in children with croup are given below.

Effectiveness of use in children with mild to moderate croup

To determine whether budesonide improves croup symptom scores and reduces the length of hospital stay, a randomized, double-blind, placebo-controlled trial was conducted in 87 children (aged 7 months to 9 years) hospitalized with a clinical diagnosis of croup. Children were given an initial dose of budesonide (2 mg) or placebo, followed by a subsequent dose of budesonide 1 mg or placebo every 12 hours. Budesonide significantly improved croup symptom scores at 12 and 24 hours, and at 2 hours in patients with an initial croup symptom score of greater than 3. There was also a 33% reduction in the length of hospital stay.

A randomized, double-blind, placebo-controlled trial compared the efficacy of budesonide and placebo for the treatment of croup in 83 infants and children (aged 6 months to 8 years) hospitalized with a clinical diagnosis of croup. Patients received budesonide 2 mg or placebo every 12 hours for up to 36 hours or until discharge from the hospital. Croup symptom scores were assessed at 0, 2, 6, 12, 24, 36, and 48 hours after the initial dose. At 2 hours, patients in the budesonide and placebo groups showed similar improvements in croup symptom scores; no statistically significant difference was noted. At 6 hours, the budesonide group had statistically significantly improved croup symptom scores compared with the placebo group; this improvement was also noted at 12 and 24 hours.

Pharmacokinetics

Absorption

The systemic availability of budesonide in adults after administration of the suspension for nebulization by jet nebulizer is approximately 15% of the nominal dose and 40-70% of the dose administered to the patient. A small part of this amount is due to absorption of the drug that has been swallowed. Maximum plasma concentrations are reached approximately 10-30 minutes after the start of nebulization and are approximately 4 nmol/l after a dose of 2 mg.

Distribution

The volume of distribution of budesonide is approximately 3 l/kg. Binding to plasma proteins is on average 85-90%.

Metabolism

Budesonide undergoes extensive (≈90%) first-pass metabolism through the liver to metabolites with low glucocorticosteroid activity. The glucocorticosteroid activity of the main metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide occurs predominantly with the participation of CYP3A4, a member of the cytochrome P450 subfamily.

Breeding

Budesonide metabolites are mainly excreted by the kidneys in unchanged or conjugated form. Unchanged budesonide is not detected in the urine. In healthy adult volunteers, the systemic clearance of budesonide is high (approximately 1.2 l/min), and the terminal half-life after intravenous administration averages 2–3 hours.

Linearity

The kinetics of budesonide are dose-proportional when used in clinically relevant doses.

In a study in which patients were given 100 mg ketoconazole twice daily concomitantly with a single oral dose of 10 mg budesonide, plasma levels of the latter increased on average 7.8-fold. There is no information on a similar type of interaction with inhaled budesonide, but a significant increase in plasma levels is expected.

Children

In children aged 4–6 years with bronchial asthma, the systemic clearance of budesonide is approximately 0.5 l/min. The clearance in children (per 1 kg of body weight) is approximately 50% higher than in adults. The terminal half-life of budesonide in children with bronchial asthma after inhalation is approximately 2.3 hours. Approximately the same indicator is observed in healthy volunteers. After using budesonide using a jet nebulizer, the systemic availability of budesonide in children with bronchial asthma aged 4–6 years is approximately 6% of the nominal dose and 26% of the dose delivered to the patient. The systemic availability in children is approximately half that in adults.

In children aged 4–6 years with bronchial asthma, the maximum plasma concentration is reached within 20 minutes after the start of the nebulization and is approximately 2.4 nmol/l after a single dose of 1 mg. Budesonide exposure (Cmax and AUC) after a single dose of 1 mg by nebulization in children aged 4–6 years are comparable to those in healthy adult volunteers who received the same dose of budesonide through the same nebulization system.

Indication

The drug contains a potent non-halogenated corticosteroid - budesonide, intended for the treatment of bronchial asthma in patients for whom the use of inhalers with compressed air atomization of medicinal substances or in the form of a dry powder dosage form is ineffective or impractical.

BUDESONIDE-INTELI NEB is also recommended for use in infants and children with croup (a complication of acute viral upper respiratory tract infection, also known as laryngotracheobronchitis or subligamentous laryngitis), which is an indication for hospitalization.

Contraindication

Hypersensitivity to budesonide or to any other ingredient of the drug.

Interaction with other medicinal products and other types of interactions

Limited data on a similar interaction with high doses of inhaled budesonide demonstrate that with concomitant use of itraconazole at a dose of 200 mg once daily, administration of inhaled budesonide (single dose of 1000 mcg) leads to a significant increase in the concentration of the substance in the blood plasma (on average 4-fold).

In women who were simultaneously taking estrogens or hormonal contraceptives, the concentration of budesonide in the blood plasma increased and the effect of corticosteroids was enhanced, however, when budesonide was used together with low doses of combined oral contraceptives, this effect was absent.

Due to possible suppression of adrenal function, the ACTH stimulation test for the diagnosis of pituitary insufficiency may give false results (low values).

Children

Interaction studies were conducted only with adults.

Application features

The drug should be used with caution in patients with active or inactive pulmonary tuberculosis and fungal or viral infections of the respiratory tract.

Patients not dependent on steroids. Therapeutic effect is usually achieved within 10 days. Patients with excessive bronchial mucus secretion may initially be given a short (about 2 weeks) additional course of oral corticosteroids. After a course of oral drugs, budesonide as monotherapy may be sufficient treatment.

Steroid-dependent patients. The switch from oral steroids to budesonide can be initiated when the patient is in a relatively stable phase of the disease. In such cases, BUDESONID-INTELI NEB should be used in combination with the oral steroid at the dose previously used for approximately 10 days.

The dose of oral steroids should then be gradually reduced (e.g. by 2.5 mg prednisolone or equivalent every month) until the lowest possible dose is reached. In many cases, complete replacement of oral steroids with budesonide is possible.

When switching from oral steroid therapy to budesonide, in most cases there is a decrease in systemic corticosteroid action, which may lead to the appearance of allergic or arthritic symptoms such as rhinitis, eczema and muscle and joint pain. Specific treatment should be prescribed for these conditions. In isolated cases, symptoms such as fatigue, headache, nausea, vomiting may occur, indicating systemic glucocorticosteroid insufficiency. In such cases, a temporary increase in the dose of the oral steroid may sometimes be necessary.

As with other inhalation therapy, paradoxical bronchospasm, accompanied by increased wheezing immediately after the procedure, may occur. If this occurs, treatment with inhaled budesonide should be discontinued immediately and the patient assessed and, if necessary, alternative therapy initiated.

Patients who have required emergency high-dose corticosteroid therapy or long-term treatment with inhaled corticosteroids at the highest recommended dose are also at risk of developing adrenal insufficiency. These patients may develop symptoms of adrenal insufficiency during periods of severe stress. Additional systemic corticosteroid therapy may be considered in stressful situations or during elective surgery.

Systemic effects may occur with any inhaled corticosteroid, especially when high doses are used for long periods of time. The likelihood of such effects is much lower with inhaled corticosteroids than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataracts and glaucoma, and, less commonly, a number of psychological and behavioral disorders, including psychomotor hyperactivity, sleep disorders, anxiety, depression, or aggression (especially in children). Therefore, the dose of inhaled corticosteroids should be titrated to the lowest effective dose at which effective control of bronchial asthma is maintained.

Budesonide is not indicated for the rapid relief of acute asthma episodes requiring short-acting inhaled bronchodilators. If the patient is not responding to short-acting bronchodilators or if they require more inhalations than usual, medical intervention is necessary. In such a situation, consideration should be given to increasing the usual therapy, for example by increasing the dose of inhaled budesonide or adding a long-acting beta-agonist or a course of oral glucocorticosteroids.

However, plasma clearance after intravenous administration of budesonide was similar in patients with liver cirrhosis and in healthy volunteers. After oral administration, systemic bioavailability of budesonide increased due to impaired liver function due to reduced first-pass metabolism. The clinical significance of these changes for budesonide treatment is not fully understood, as data on inhaled budesonide are lacking, but an increase in plasma levels and, consequently, an increased risk of systemic adverse reactions can be expected.

In vivo studies have shown that oral administration of ketoconazole and itraconazole (known inhibitors of CYP3A4 activity in the liver and intestinal mucosa) leads to an increase in systemic exposure to budesonide. Concomitant treatment with ketoconazole, itraconazole, HIV protease inhibitors or other potent CYP3A4 inhibitors should be avoided. If this is not possible, 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 (see section 4.5).

The nebulizer chamber and nozzle or mask should be washed after each use with hot water and a mild detergent, then rinsed thoroughly and dried.

Oral candidiasis may develop during treatment with inhaled corticosteroids. This infection may require the use of appropriate antifungal agents and, in some patients, may require discontinuation of treatment (see also section 4.2).

Children

Impact on growth

Regular monitoring of growth is recommended in children receiving long-term treatment with inhaled corticosteroids. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid to the lowest possible dose at which effective control of bronchial asthma is maintained. The benefits of corticosteroid therapy should be carefully weighed against the possible risk of growth suppression. In addition, it is important to refer the patient for consultation with a pediatric pulmonologist.

Ability to influence reaction speed when driving vehicles or other mechanisms

Budesonide has no or negligible influence on the ability to drive and use machines.

Use during pregnancy or breastfeeding

Pregnancy

The results of a large prospective epidemiological study and the experience of international use of the drug in the post-registration period indicate that treatment with inhaled budesonide during pregnancy did not lead to undesirable effects on the health of the fetus/newborn child.

Animal studies have shown that glucocorticosteroids can cause developmental disorders. However, these data are not considered relevant for humans at recommended doses, but inhaled budesonide therapy should be reviewed regularly and the drug should be used at the lowest effective dose.

The use of budesonide during pregnancy requires careful consideration of the benefits to the woman and the risks to the fetus. Inhaled glucocorticosteroids should be preferred to oral glucocorticosteroids due to the lower systemic effects when used in doses required to achieve the same respiratory response.

Breastfeeding period

Budesonide passes into breast milk. However, when using therapeutic doses of budesonide, no effects on the breast-fed child are expected. BUDESONIDE-INTELI NEB can be used during breast-feeding.

Maintenance treatment with inhaled budesonide (200 or 400 mcg twice daily) in women with bronchial asthma who are breastfeeding results in only a small systemic exposure of budesonide in breastfed infants.

In a pharmacokinetic study, the calculated daily dose in the infant was 0.3% of the maternal daily dose for both doses, and the mean plasma concentration in the infant was estimated to be one-six-hundredth of the concentration observed in the maternal plasma, assuming full oral bioavailability in the infant. Budesonide concentrations in all infant plasma samples were below the limit of quantification.

Considering the data on budesonide for inhalation administration and the fact that budesonide exhibits linear PK properties within the therapeutic dose range after nasal, inhalation, oral or rectal administration, it is expected that exposure to budesonide in breast-fed infants at therapeutic doses will be low.

Method of administration and doses

The dose administered to the patient depends on the nebulization equipment used. The nebulization time and the dose delivered depend on the flow rate, the volume of the nebulizer chamber and the fill volume. The air flow rate through the nebulizer device used should be 6–8 liters per minute. The appropriate fill volume for most nebulizers is 2–4 ml. The dose should be reduced to the minimum necessary to maintain adequate control of bronchial asthma. The highest dose (2 mg per day) in children under 12 years of age should be prescribed only in case of severe asthma and for a limited period of time.

Bronchial asthma

Beginning of therapy

At the beginning of treatment, during periods of exacerbation of bronchial asthma and when reducing or discontinuing oral glucocorticosteroids, the recommended dose is:

Adults (including the elderly): usually 1–2 mg twice a day. In very severe cases, the dose may be further increased; Children over 12 years of age: the same dosage as for adults; Children from 6 months to 12 years of age: 0.5–1 mg twice a day.

Supportive therapy

The maintenance dose should be selected individually and should be equal to the lowest dose at which the patient is free of symptoms of the disease.

Adults (including elderly patients) and children over 12 years of age: 0.5–1 mg twice daily.

Children aged 6 months to 12 years: 0.25–0.5 mg twice daily.

Patients taking oral glucocorticoids as maintenance therapy

BUDESONID-INTELI NEB allows the patient to withdraw or significantly reduce the dose of oral corticosteroids while maintaining control of asthma. The patient should be relatively stable before starting the transition from oral steroids. A high dose of budesonide nebulised should be used for approximately 10 days in combination with the previously used oral steroid dose. After this, the oral steroid dose should be gradually reduced to the lowest possible level, for example by 2.5 mg prednisolone or equivalent per month. Often, the oral steroid can be completely discontinued by replacing it with BUDESONID-INTELI NEB. For more information on withdrawal of oral corticosteroids, see the section “Special instructions for use”.

Dosage features

The drug can be mixed with 0.9% saline and with nebulizer solutions containing terbutaline, salbutamol, fenoterol, acetylcysteine, sodium cromoglicate or ipratropium bromide. The mixture should be used within 30 minutes.

DOSAGE RECOMMENDATIONS

For patients for whom it is desirable to increase the therapeutic effect, especially patients without a large amount of mucus in the respiratory tract, it is recommended to increase the dose of budesonide instead of combination treatment with oral corticosteroids, which is associated with a lower risk of systemic side effects.

Croup

For children with croup, the usual dose is 2 mg of nebulized budesonide. This dose should be administered as a single dose or as two 1 mg doses 30 minutes apart. The dose may be repeated every 12 hours for a maximum of 36 hours or until clinical improvement.

Method of application

The drug BUDESONID-INTELI NEB should only be used with nebulizers suitable for this purpose.

The container must be detached from the strip, gently shaken and opened by breaking off the tip tab. Carefully squeeze the contents of the container into the nebulizer chamber. Discard the empty container and cover the nebulizer chamber with the cap.

BUDESONIDE-INTELI NEB should be administered using a jet nebulizer with a nozzle or a suitable breathing mask. The nebulizer should be connected to an air compressor that provides sufficient air flow (6–8 l/min) and the fill volume should be 2–4 ml.

Note: It is important that the patient:

carefully read the instructions for use given in the patient information leaflet included in the packaging of each nebulizer; understood that ultrasonic nebulizers are not suitable for administering BUDESONID-INTELI NEB and therefore their use is not recommended; was informed about the possibility of mixing BUDESONID-INTELI NEB with 0.9% saline and with nebulization solutions containing terbutaline, salbutamol, fenoterol, acetylcysteine, sodium cromoglycate and ipratropium bromide, and was also aware of the need to use the mixture within 30 minutes; rinsed the oral cavity with water after inhaling the prescribed dose to minimize the risk of oropharyngeal candidiasis; washed the face with water after using the respiratory mask to prevent skin irritation; properly washed and stored the nebulizer according to the manufacturer's instructions.

Children

BUDESONID-INTELI NEB should be used in children according to indications (see sections “Indications” and “Method of administration and dosage”).

Overdose

BUDESONIDE-INTELI NEB contains 0.1 mg/ml disodium edetate, which has been shown to cause bronchoconstriction at levels exceeding 1.2 mg/ml. Acute overdose of budesonide, even at excessive doses, is unlikely to be a clinically significant problem.

Adverse reactions

The following definitions were used to assess the frequency of occurrence of undesirable effects. Frequency is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Table 2

Adverse reactions

see description of individual adverse reactions below; facial skin irritation

** see Children section below

*** occasionally in children

Description of selected adverse reactions

Oropharyngeal candidiasis is caused by drug deposition. Rinsing the mouth with water after each use of the drug minimizes this risk.

As with any inhalation therapy, the development of paradoxical bronchospasm is very rare (see section "Special warnings and precautions for use").

Occasionally, when using a nebulizer with a breathing mask, hypersensitivity reactions in the form of facial skin irritation have been reported. To prevent irritation, wash your face after using the mask.

There is an increased risk of pneumonia in patients with newly diagnosed COPD who are initiated on inhaled corticosteroids. However, a weighted evaluation of eight pooled clinical trials involving 4,643 patients with COPD treated with budesonide and 3,643 patients randomized to treatment without inhaled corticosteroids did not demonstrate an increased risk of pneumonia. The results of 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 for prolonged periods. This effect is much less likely with inhaled treatment than with oral corticosteroids. Possible systemic effects include decreased bone mineral density. The effect is likely to be dose-related, time of exposure, concomitant and previous corticosteroid treatment, and individual sensitivity.

Children

Due to the risk of growth retardation in children, growth monitoring should be performed in such patients as described in the section "Special warnings and precautions for use".

Expiration date

3 years.

After opening the envelope, the containers contained therein should be used within 3 months. After this period, the remaining product should be disposed of. The contents of an opened container should be used within 12 hours. After this period, the remaining product should be disposed of.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C, protected from light. Keep out of the reach of children. Keep containers in an envelope to protect from light.

Packaging

2 ml in a single-dose container; 5 containers in an aluminum foil envelope; 4 envelopes in a cardboard box.

Vacation category

According to the recipe.

Producer

GENETIK S.P.A.

Location of the manufacturer and its business address

CONTRADA CANFORA, FISHANO, 84084, Italy.