Pulmicort suspension for nebulization 0.25 mg/ml container 2 ml No. 20

Instructions Pulmicort suspension for nebulization 0.25 mg/ml container 2 ml No. 20

Composition

active ingredient: budesonide;

1 ml of suspension for nebulization contains 0.25 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: easily resuspended white or almost white suspension filled into single-dose containers made of low-density polyethylene.

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 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 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 involving healthy volunteers, a dose-dependent effect on plasma and urinary cortisol levels was observed when using Pulmicort Turbuhaler. Pulmicort Turbuhaler, when used in recommended doses, has significantly less effect on adrenal function than prednisone at a dose of 10 mg, which is confirmed by ACTH tests.

Children

Clinical application: bronchial asthma

The effectiveness of Pulmicort 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 preventive treatment of persistent asthma.

Clinical application: croup

A number of studies have compared Pulmicort with placebo in children with croup. Examples of representative studies that have examined the use of Pulmicort in the treatment of children with croup are given below.

Effectiveness of use in children with mild to moderate croup

To determine whether Pulmicort improves croup symptom scores and whether such treatment reduces the length of hospital stay, a randomized, double-blind, placebo-controlled trial was conducted in 87 children (aged 7 months to 9 years) who were hospitalized with a clinical diagnosis of croup. Participants received an initial dose of Pulmicort (2 mg) or placebo, followed by a dose of Pulmicort 1 mg or placebo every 12 hours. Pulmicort significantly improved croup scores at 12 and 24 hours, as well as at 2 hours in patients with an initial croup symptom score of greater than 3. The length of hospital stay was also reduced by 33%.

A randomized, double-blind, placebo-controlled study was conducted to compare the efficacy of Pulmicort and placebo in 83 infants and children (aged 6 months to 8 years) hospitalized with a clinical diagnosis of croup. Patients received Pulmicort 2 mg or placebo every 12 hours for up to 36 hours or until discharge. The total croup symptom score was determined before drug administration and 2, 6, 12, 24, 36, and 48 hours after the initial dose. After 2 hours, the Pulmicort and placebo groups showed similar improvements in croup symptom scores, with no statistically significant difference between the groups. After 6 hours, the score on croup symptoms in the Pulmicort group was significantly better than in the placebo group, and this improvement compared to placebo was equally evident also after 12 and 24 hours.

Pharmacokinetics

Absorption

The systemic availability of budesonide after administration of Pulmicort suspension for inhalation via a 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. The maximum plasma concentration is reached approximately 10-30 minutes after the start of nebulization and is approximately 4 nmol/l after administration of 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 excreted mainly 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 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 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. In children with bronchial asthma, the terminal half-life of budesonide after inhalation is approximately 2.3 hours. Approximately the same figure is observed in healthy volunteers. In patients aged 4–6 years with bronchial asthma, the systemic availability of budesonide after administration of Pulmicort inhalation suspension 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 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 is comparable to those in healthy adult volunteers who received the same dose of budesonide through the same nebulization system.

Indication

Pulmicort 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 inappropriate.

Pulmicort is also recommended for use in infants and children with croup (a complication of an 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 when itraconazole is co-administered at a dose of 200 mg once daily, administration of inhaled budesonide (single dose of 1000 mcg) leads to a significant increase in plasma concentrations (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 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 without steroid dependence. The therapeutic effect is usually achieved within 10 days. Patients with excessive bronchial mucus secretion may initially be given a short-term (about 2 weeks) additional course of oral corticosteroids. After a course of oral drugs, Pulmicort as monotherapy may be sufficient treatment.

Steroid-dependent patients. The transition from oral steroids to Pulmicort can be initiated when the patient is in a relatively stable phase of the disease. In such cases, Pulmicort 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 every month) until the lowest possible dose is reached. In many cases, complete replacement of oral steroids with Pulmicort is possible.

When switching from oral steroid therapy to Pulmicort, 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 disturbances, 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.

Pulmicort is not intended for the rapid relief of acute episodes of bronchial asthma requiring the use of 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 prescribing a course of oral glucocorticosteroids.

However, plasma clearance after intravenous administration of budesonide was the same in patients with liver cirrhosis and in healthy volunteers. After oral administration, the systemic bioavailability of budesonide increased due to impaired liver function due to a decrease in first-pass metabolism. The clinical significance of these changes for Pulmicort treatment is not fully understood, since 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 necessitate discontinuation of treatment (see also section 4.2).

Children

Impact on growth

In children receiving long-term treatment with inhaled corticosteroids, regular monitoring of growth is recommended. 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

Pulmicort 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-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 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 mother and the risks to the fetus. Inhaled corticosteroids should be preferred over oral corticosteroids due to the lower systemic effects at doses required to produce the same respiratory response.

Breastfeeding period

Budesonide passes into breast milk. However, when using therapeutic doses of Pulmicort, no effects on the breast-fed child are expected. Pulmicort 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 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

Dosage

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 filling volume. The air flow rate through the device used for nebulization should be 6–8 liters per minute. The appropriate filling volume for most nebulizers is 2–4 ml. The dosage of Pulmicort should be adjusted depending on the individual needs of the patient. 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 of Pulmicort is:

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

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.

Patients taking oral glucocorticoids as maintenance therapy

Pulmicort 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 Pulmicort is given for approximately 10 days in combination with the dose of oral steroid previously used. After this, the dose of oral steroids 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 Pulmicort. For more information on withdrawal of oral corticosteroids, see the section "Special instructions for use".

Dosage features

Pulmicort 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 Pulmicort 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 is 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

Pulmicort is used only with suitable nebulizers.

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.

Pulmicort 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 Pulmicort and are therefore not recommended for use; was informed about the possibility of mixing Pulmicort 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 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 cleaned and stored the nebulizer according to the manufacturer's instructions.

Children

Pulmicort is used in children according to indications.

Overdose

Pulmicort contains 0.1 mg/ml of edetate disodium, which has been shown to cause bronchoconstriction at levels exceeding 1.2 mg/ml. Acute overdose of Pulmicort, 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. The 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).

* 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 if 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 depend on the dose, time of exposure, concomitant and previous corticosteroid treatment, and individual sensitivity.

Children

Due to the risk of growth retardation in children, growth monitoring in pediatric patients is necessary as described in the section "Special warnings and precautions for use".

Expiration date

2 years.

Once the envelope is opened, the containers contained therein should be used within 3 months. If only 1 ml of suspension is used, the remaining suspension is not sterile.

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.

Keep containers in an 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 its business address

Forskargatan 18, Sodertalje, 15185, Sweden.