Budesonide-Astrazeneca suspension for inhalation 0.5 mg/ml nebules 2 ml No. 20

Instructions Budesonide-Astrazeneca suspension for inhalation 0.5 mg/ml nebules 2 ml No. 20

Composition

active ingredient: budesonide;

1 ml of suspension for nebulization contains 0.5 mg of budesonide;

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

Dosage form

Suspension for spraying.

Main physicochemical properties: easily resuspended suspension, white or almost white in color, filled into single-dose containers made of low-density polyethylene.

Pharmacotherapeutic group

Inhalants used for the treatment of obstructive airway diseases. Glucocorticoids. ATX code RO3B 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 asthmatic patients comparing inhaled and oral budesonide formulations at doses designed to achieve similar systemic bioavailability showed a statistically significant superiority of inhaled budesonide over oral budesonide compared to placebo. Thus, the therapeutic effect of standard doses of inhaled budesonide can be largely explained by direct action on the airways.

In a challenge study, pretreatment with budesonide for four 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

In short-term studies, a small and usually transient reduction in growth rate was observed, usually occurring within the first year of treatment. Limited data from long-term studies suggest that most children and adolescents treated with inhaled budesonide eventually reached their adult height. However, in one study, children treated with high-dose inhaled budesonide by dry powder inhaler (400 mcg daily) for 6 years without titration to the lowest effective dose were on average 1.2 cm shorter in adulthood than those treated with placebo for the same period. For information on titration to the lowest effective dose and on monitoring growth in children, see section 4.4.

Effect on plasma cortisol concentration

In studies in healthy volunteers, Budesonide AstraZeneca had a dose-dependent effect on plasma and urinary cortisol levels. Budesonide AstraZeneca at recommended doses has significantly less effect on adrenal function than prednisone 10 mg, as confirmed by ACTH assays.

Children

Clinical application: bronchial asthma

Budesonide AstraZeneca has been studied in numerous studies that have demonstrated its effectiveness in adults and children, given once or twice daily, for the prophylactic treatment of persistent asthma. Some representative examples of these studies are provided below.

Clinical application: croup

A number of studies have compared treatment with Budesonide AstraZeneca with placebo in children with croup. Examples of representative studies that have looked at the use of Budesonide AstraZeneca in children with croup are given below.

A randomised, double-blind, placebo-controlled trial was conducted to determine whether Budesonide AstraZeneca improves symptoms of croup and reduces the length of hospital stay, in 87 children (aged 7 months to 9 years) admitted to hospital with a clinical diagnosis of croup. Participants received an initial dose of Budesonide AstraZeneca (2 mg) or placebo, followed by a dose of Budesonide AstraZeneca 1 mg or placebo every 12 hours. Budesonide AstraZeneca statistically significantly improved croup scores at 12 and 24 hours, and at 2 hours in patients with an initial croup score of greater than 3. The length of hospital stay was also reduced by 33%.

Effectiveness of use in children with moderate and severe croup

A randomised, double-blind, placebo-controlled trial was conducted to compare the efficacy of treatment with Budesonide AstraZeneca and placebo in 83 infants and children (aged 6 months to 8 years) admitted to hospital with a clinical diagnosis of croup. Patients received Budesonide AstraZeneca 2 mg or placebo every 12 hours for up to 36 hours or until discharge. The total croup symptom score was assessed before treatment and at 0, 2, 6, 12, 24, 36 and 48 hours after the initial dose. At 2 hours, the Budesonide AstraZeneca and placebo groups showed similar improvements in croup symptom scores, with no statistically significant difference between the groups. At 6 hours, the score for croup symptoms in the Budesonide AstraZeneca group was statistically significantly better than in the placebo group, and this improvement compared to placebo was equally evident at 12 and 24 hours.

Pharmacokinetics

Absorption

The systemic availability of budesonide after administration of Budesonide AstraZeneca inhalation suspension via a jet nebuliser is approximately 15% of the nominal dose and 40-70% of the dose delivered to the patient. A small proportion of this is due to absorption of swallowed medicinal product. Peak plasma concentrations are achieved approximately 10-30 minutes after the start of nebulisation and are approximately 4 nmol/l after a 2 mg dose.

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 CYP3A, a member of the cytochrome P450 subfamily.

Breeding

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

Linearity

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

In a study in which patients were also given 100 mg ketoconazole twice daily, an average 7.8-fold increase in plasma budesonide levels was observed after oral administration (single dose of 10 mg). There is no information on interactions of this type with inhaled budesonide, but a significant increase in plasma levels is expected.

Children

In children aged 4–6 years with asthma, the systemic clearance of budesonide is approximately 0.5 l/min. The clearance in children (per kg body weight) is approximately 50% higher than in adults. In children with asthma, the terminal half-life of budesonide after inhalation is approximately 2.3 hours. Approximately the same figure is observed in healthy adults. In patients aged 4–6 years with asthma, the systemic availability of budesonide after administration of Budesonide AstraZeneca suspension for inhalation via a jet nebulizer (Pari LC Jet Plus® with Pari Master® compressor) 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 healthy 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 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 adults who received the same dose of budesonide via the same nebulization system.

Indication

Budesonide AstraZeneca 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 the active substance or any of the excipients.

Interaction with other medicinal products and other types of interactions

Budesonide is primarily metabolised by CYP3A4. Concomitant use with CYP3A inhibitors, such as itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products, is expected to increase the risk of systemic corticosteroid effects (see sections 4.4 and 5.1).

The combination of Budesonide AstraZeneca with potent CYP3A inhibitors should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid-related side effects, in which case patients should be monitored for systemic corticosteroid-related side effects. When Budesonide AstraZeneca is used concomitantly with antifungal agents (such as itraconazole and ketoconazole), the interval between administration of these agents should be as long as possible. A reduction in the dose of budesonide may be considered.

Limited data on a similar interaction with high doses of inhaled budesonide demonstrate that when itraconazole 200 mg once daily is coadministered, administration of inhaled budesonide (single dose 1000 mcg) results in a significant increase in plasma concentrations (on average fourfold).

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.

Because adrenal function may be suppressed, the ACTH stimulation test, intended to diagnose pituitary insufficiency, may give false results (low values).

Children

Interaction studies were conducted only in 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. The therapeutic effect is usually achieved within 10 days. Patients with excessive bronchial mucus production may initially be given a short-term (approximately 2 weeks) additional course of oral corticosteroids. After a course of oral medications, Budesonide AstraZeneca as monotherapy may be sufficient treatment.

Steroid-dependent patients. The switch from oral steroids to Budesonide AstraZeneca can be initiated when the patient is in a relatively stable phase of the disease. Budesonide AstraZeneca is 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 each month) to the lowest possible level. In many cases, complete replacement of oral steroids with Budesonide AstraZeneca is possible.

When switching from oral steroid therapy to Budesonide AstraZeneca, 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 initiated for these conditions. Usually, insufficient effect of glucocorticosteroid therapy can be suspected if symptoms such as fatigue, headache, nausea, vomiting occur, although this is rare. In such cases, a temporary increase in the dose of oral glucocorticosteroids 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.

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 disturbances, anxiety, depression, or aggression (especially in children). Therefore, it is important to titrate the dose of inhaled corticosteroid to the lowest dose at which effective control of bronchial asthma is maintained.

Budesonide AstraZeneca is not intended for the rapid relief of acute asthma episodes requiring short-acting inhaled bronchodilators. If a patient is not responding to short-acting bronchodilators or is requiring 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.

Decreased liver function may affect the elimination of glucocorticosteroids from the body, as the rate of elimination is reduced and systemic exposure is increased. It is necessary to remember about the possible development of side effects.

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 treatment with Budesonide AstraZeneca is not fully understood, as data on inhaled budesonide are lacking, but an increase in plasma levels and therefore an increased risk of systemic adverse reactions can be expected.

Concomitant use with CYP3A inhibitors, such as itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products is expected to increase the risk of systemic corticosteroid side effects. This combination should be avoided unless the benefit outweighs the increased risk; in which case patients should be monitored for systemic corticosteroid-related side effects. This is of limited clinical significance during short-term (1-2 weeks) treatment with itraconazole or ketoconazole or other potent CYP3A inhibitors, but should be considered during long-term treatment. A reduction in the budesonide dose should also be considered (see section 4.5).

The nebulizer chamber should be cleaned after each use. Wash the nebulizer chamber and the mouthpiece or breathing mask in hot water with a mild detergent. Rinse thoroughly and dry by connecting the nebulizer chamber to the compressor or air intake.

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

Pneumonia in patients with COPD

An increased incidence of pneumonia, including pneumonia requiring hospitalization, has been observed in patients with COPD receiving inhaled corticosteroids.

There is evidence of an increased risk of pneumonia with increasing corticosteroid dose, but this has not been conclusively demonstrated in any of the studies.

For inhaled corticosteroid drugs, there is no comprehensive clinical evidence of intraclass differences in the magnitude of the risk of developing pneumonia.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical signs of such infections overlap with symptoms of COPD exacerbations.

Risk factors for developing pneumonia in patients with COPD include smoking, older age, low body mass index (BMI), and severe COPD.

Vision impairment

Visual disturbances have been reported with systemic and topical corticosteroids. If a patient presents with symptoms such as blurred vision or other visual disturbances, an ophthalmologist should be consulted to evaluate possible causes, which may include cataracts, glaucoma, or rare diseases such as central serous chorioretinopathy (CSR), which have been reported following systemic or topical corticosteroid use.

Children

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.

Use during pregnancy or breastfeeding

Pregnancy

Most results of prospective epidemiological studies and experience of international use of the drug in the post-marketing 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 therapy with inhaled budesonide should be reviewed regularly and the lowest effective dose used. It is important for both the fetus and the mother that adequate asthma treatment is maintained during pregnancy. As with the use of other drugs during pregnancy, the benefits of budesonide to the mother should be weighed against the risks to the fetus.

Inhaled glucocorticosteroids should be preferred over oral glucocorticosteroids due to the lower systemic effects when used in doses required to achieve the same respiratory response.

Breast-feeding

Budesonide passes into breast milk. However, at therapeutic doses of Budesonide AstraZeneca, no effects on the breast-fed child are expected. Budesonide AstraZeneca 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 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 inhaled budesonide and the fact that budesonide exhibits linear PK properties within the therapeutic dose range after nasal, inhaled, oral or rectal administration, it is expected that exposure to budesonide in breast-fed infants at therapeutic doses will be low.

Ability to influence reaction speed when driving vehicles or other mechanisms

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

Method of administration and doses

Dosage

The dosage of Budesonide AstraZeneca should be adjusted according to the individual needs of the patient.

Dosage regimens.

The dose administered to the patient depends on the nebulisation equipment used. The nebulisation time and the dose delivered depend on the flow rate, the volume of the nebuliser chamber and the fill volume. The air flow rate through the nebuliser should be 6-8 litres per minute. The appropriate fill volume for most nebulisers is 2-4 ml. The dosage of Budesonide AstraZeneca should be adjusted to the individual needs of the patient. The dose should be reduced to the minimum necessary to maintain adequate control of asthma. The highest dose (2 mg per day) should be given to children under 12 years of age only in 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 of Budesonide AstraZeneca is:

Adults (including the elderly): usually 1–2 mg twice daily. In very severe cases, the dose may be further increased.

Children

Children over 12 years of age: dosage is the same as for adults.

Children aged 6 months to 12 years: 0.5–1 mg twice daily.

Supportive therapy

The maintenance dose should be selected individually and equal to the lowest dose at which the patient has no 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.

Budesonide AstraZeneca allows the patient to be withdrawn or significantly reduced from oral corticosteroids while maintaining control of asthma. The patient should be relatively stable before switching from oral steroids to Budesonide AstraZeneca. A high dose of Budesonide AstraZeneca is given for approximately 10 days in combination with the previous oral steroid dose. The oral steroid dose should then be gradually reduced to the lowest possible dose (e.g. 2.5 mg prednisolone or equivalent per month). The oral steroid can often be withdrawn completely by switching to Budesonide AstraZeneca. For more information on withdrawal of oral corticosteroids, see section 4.4.

Dose splitting and mixing with other drugs

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

Table 1

Dosage recommendations

For patients who wish 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 AstraZeneca instead of combination treatment with oral corticosteroids, which is associated with a lower risk of systemic side effects.

Croup

For infants and children with croup, the usual dose is 2 mg of nebulized budesonide. This dose is given 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

Budesonide AstraZeneca is only used with suitable nebulizers.

Instructions for proper use

The container must be detached from the strip, gently shaken and opened by breaking off the tip tab. The contents of the container are carefully squeezed into the nebulizer chamber. The empty container is discarded, and the nebulizer chamber is covered with a lid.

Budesonide AstraZeneca should be administered using a jet nebuliser with a nozzle or suitable breathing mask. The nebuliser should be connected to an air compressor providing 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 medical use of the medicinal product, which are included in the packaging of each nebulizer;

understood that ultrasonic nebulizers are not suitable for administering the drug Budesonide AstraZeneca, and therefore their use is not recommended;

was informed about the possibility of mixing the drug Budesonide AstraZeneca with 0.9% saline and with nebulizer 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 mouth with water after inhalation to minimize the risk of developing oropharyngeal candidiasis;

washed the face with water after using the breathing mask to prevent skin irritation;

properly rinsed and stored the nebulizer according to the manufacturer's instructions.

Children

Budesonide AstraZeneca is used in children according to indications (see sections “Indications” and “Method of administration and dosage”)

Overdose

Budesonide AstraZeneca contains 0.1 mg/ml disodium edetate, which has been shown to cause bronchoconstriction at levels exceeding 1.2 mg/ml. Acute overdose with Budesonide AstraZeneca, even at excessive doses, would not be a clinically significant problem.

Adverse reactions

The following definitions were used to assess the frequency of adverse reactions: 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 by system organ class and frequency

* See below for a description of specific adverse reactions; facial skin irritation.

** See the "Children" section below.

*** Based on frequency reported in clinical trials.

**** Rarely in children.

Signs or symptoms of systemic glucocorticosteroid side effects may occasionally occur with inhaled glucocorticosteroids, which is likely to depend on the dose, time of exposure, concomitant and previous exposure to corticosteroids, and individual sensitivity (see section "Special warnings and precautions for use").

Description of selected adverse reactions

Oropharyngeal candidiasis is caused by drug deposition on mucous membranes. The patient should be instructed to rinse the mouth with water after each inhalation of the maintenance dose to minimize 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.

Also, in placebo-controlled studies, cataracts were uncommonly reported in the placebo group.

In the pooled clinical trials, 13,119 patients received inhaled budesonide and 7,278 patients received placebo. The incidence of anxiety was 0.52% for inhaled budesonide and 0.63% for placebo; the incidence of depression was 0.67% for inhaled budesonide and 1.15% for placebo.

Children

Due to the risk of growth retardation in children, the child's growth should be monitored as described in the section "Special warnings and precautions for use".

Reporting of adverse reactions

It is important to report suspected adverse reactions during the post-marketing period of a medicinal product. This allows for continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Expiration date

24 months.

Use within 3 months after opening the foil envelopes.

If only 1 ml of suspension is used, the remaining suspension is no longer sterile and should be discarded immediately.

Storage conditions

Store at a temperature not exceeding 30 ° C. Do not freeze.

Keep out of reach of children.

Containers should be stored in an upright position.

Store containers in a foil envelope to protect from light.

Packaging

2 ml in a low-density polyethylene container; 5 containers connected together in an aluminum foil envelope; 4 envelopes in a cardboard box.

Vacation category

According to the recipe.

Producer

AstraZeneca AB.

Location of the manufacturer and address of its place of business

Forskargatan 18, Sodertalje, 151 36, Sweden.