Instructions Benodil suspension for inhalation 0.5 mg / ml 2 ml No. 20
Composition
active ingredient: budesonide;
1 ml of suspension for nebulization contains 0.5 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: homogeneous white suspension.
Pharmacotherapeutic group
Other inhalation agents used in obstructive airway diseases. Glucocorticoids. ATX code R03B A02.
Pharmacological properties
Pharmacodynamics
Budesonide is a glucocorticoid 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 glucocorticoids in the treatment of 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 by inhaler, improvements in lung function are achieved within a few hours. It has been shown that after therapeutic use of inhaled budesonide orally, 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 asthma attacks that may be triggered by exercise.
Growth
Limited data from long-term studies suggest that most children and adolescents who use inhaled budesonide eventually reach their appropriate adult height.
However, a small initial, albeit transient, growth retardation (approximately 1 cm) has been observed, most of which occurs within the first year of treatment (see section 4.4).
Effect on plasma cortisol concentration
In studies with healthy volunteers, Benodil showed a dose-dependent effect on plasma and urinary cortisol levels. Benodil, when used in recommended doses, has significantly less effect on adrenal function than prednisone at a dose of 10 mg, as confirmed by ACTH 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 1–2 times a day for the prophylactic treatment of persistent asthma.
Clinical application: croup
Several studies have compared budesonide with placebo in children with croup. Representative examples of studies investigating the use 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) who were hospitalized with a clinical diagnosis of croup. Participants received 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 scores at 12 and 24 hours, and 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 trial was conducted to compare the efficacy of budesonide and placebo 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. The total croup symptom score was determined before drug administration and 2, 6, 12, 24, 36, and 48 hours after the initial dose. At 2 hours, the budesonide and placebo groups showed similar improvements in croup symptom scores, with no statistically significant difference between the groups. At 6 hours, the budesonide group had significantly better croup symptom scores than the placebo group, and this improvement over placebo was equally evident at 12 and 24 hours.
Pharmacokinetics
Absorption
The systemic availability of budesonide after administration of Benodil inhalation suspension via a compressor-type jet nebulizer is approximately 15% of the total prescribed dose and 40-70% of the actual delivered dose. A small part of this amount is due to absorption of the drug that has been swallowed. The maximum concentration in the blood plasma is reached approximately 10-30 minutes after the start of nebulization and is 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 to metabolites with low glucocorticoid activity. The glucocorticoid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide occurs predominantly with the participation of the hepatic enzyme CYP3A4, which belongs to 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 interactions of this type 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 Benodil inhalation suspension via a jet nebulizer (Pari LC Jet Plus® with Pari Master® compressor) is approximately 6% of the total prescribed dose and 26% of the actual delivered dose. 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 are comparable to those in healthy adult volunteers who received the same dose of budesonide through the same nebulization system.
Indication
Benodil 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.
Benodil 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 false croup), 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
Budesonide is metabolised mainly by the hepatic enzyme CYP3A4, and inhibitors of this enzyme, such as ketoconazole and itraconazole, may increase the systemic exposure of budesonide (see sections 4.4 and 5.2). Since no data are available on dosing, it is recommended to avoid concomitant use of these medicinal products. 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 may be considered. It is likely that other potent CYP3A4 inhibitors also lead to significant increases in plasma levels of budesonide.
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 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 corticosteroids, Benodil as monotherapy may be sufficient treatment.
Steroid-dependent patients. The transition from oral steroids to Benodil can be initiated when the patient is in a relatively stable phase of the disease. In such cases, Benodil should be used in combination with the oral steroid at the dose previously used for approximately 10 days.
The dose of oral corticosteroids 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 corticosteroids with Benadyl is possible.
When switching from oral steroid therapy to Benodil, in most cases there is a decrease in the systemic effect of corticosteroids, 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 glucocorticoid insufficiency. In such cases, a temporary increase in the dose of 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.
Benodil 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 glucocorticoids.
Decreased hepatic function may affect the elimination of corticosteroids 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 deterioration of liver function due to a decrease in first-pass metabolism. The clinical significance of these changes for treatment with Benodil is not fully understood, since data on inhaled budesonide are lacking, but an increase in plasma levels of the drug 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
Do not use in children under 6 months of age.
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.
Concomitant use with CYP3A inhibitors, including those containing combistatin, is expected to increase the risk of systemic adverse effects. Concomitant use of these drugs should be avoided unless the expected benefit outweighs the risk of systemic corticosteroid adverse effects. In such cases, the patient should be monitored for these adverse effects.
Oral candidiasis may occur during treatment with inhaled corticosteroids. In these cases, appropriate antifungal therapy may be required, and in some cases, discontinuation of therapy may be necessary (see Adverse Reactions).
Vision impairment
Visual disturbances may occur with systemic and topical corticosteroids. If blurred vision or other visual disturbances occur, referral to an ophthalmologist should be considered to exclude other possible causes, including cataracts, glaucoma, and rare conditions such as central serous chorioretinopathy (CSCR), which has been reported to occur with systemic or topical corticosteroids.
Use during pregnancy or breastfeeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
Benodil 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.
The use of budesonide during pregnancy requires careful consideration of the benefits to the woman and the risks to the fetus. Inhaled glucocorticoids should be preferred over oral glucocorticoids because of their 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 Benodil, no effects on the breast-fed child are expected. Benodil can be used during breastfeeding.
Maintenance treatment with inhaled budesonide 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.
The concentration of budesonide in all infant plasma samples was 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 drug is intended for use by spraying through a compressor-type nebulizer (see below).
Dosage
The dosage of Benodil should be adjusted according to the individual needs of the patient. The dose should be reduced to the minimum necessary to maintain adequate control of bronchial asthma. In patients for whom it is desirable to increase the therapeutic effect, especially in patients without a large amount of mucus in the respiratory tract, it is recommended to increase the dose of Benodil instead of
combination treatment with oral corticosteroids, which is associated with a lower risk of systemic side effects.
Bronchial asthma
Beginning of therapy
At the beginning of treatment, during periods of exacerbation of bronchial asthma and when reducing or discontinuing oral glucocorticoids, the recommended dose of Benodil is according to Table 1.
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.
The highest dose (2 mg per day) for children under 12 years of age should be prescribed only in case of severe asthma and for a limited period of time.
Table 1
| Starting dose | Supportive therapy | Maximum daily dose |
| Children aged 6 months to 12 years | 0.5–1 mg twice daily | 0.25–0.5 mg twice daily | 2 mg |
| Children aged 12 years and over and Adults (including elderly patients) | 1–2 mg twice daily | 0.5–1 mg twice daily | 4 mg |
Patients taking oral glucocorticoids as maintenance therapy
Benodil allows the patient to withdraw or significantly reduce the dose of oral glucocorticoids while maintaining control of asthma. The patient should be relatively stable before starting the transition from oral steroids. A high dose of Benodil should be used 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 of prednisolone or equivalent per month.
Often, the oral steroid can be completely discontinued by replacing it with Benadyl. For more information on the withdrawal of oral glucocorticoids, see the section "Special instructions for use".
Dosage features
Benodil can be mixed with 0.9% saline. The mixture should be used within 30 minutes.
Table 2
The relationship between volume (ml) and dose (mg) of Benodil
| Dose | Volume of the drug Benodil, suspension for spraying in concentration | |
| 0.25 mg/ml | 0.5 mg/ml | |
| 0.25 mg | 1 ml | - |
| 0.5 mg | 2 ml | 1 ml |
| 0.75 mg | 3 ml | - |
| 1.0 mg | 4 ml | 2 ml |
| 1.5 mg | 6 ml | 3 ml |
| 2.0 mg | 8 ml | 4 ml |
Croup
For children with croup, the usual dose is 2 mg of nebulized budesonide. This dose may be 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
For use on children, it is recommended to use a face mask of the appropriate size with sufficient grip and a tight fit to the face.
The duration of inhalation and the dose delivered depend on the nature of breathing and the amount of drug introduced into the nebulizer.
The ampoule (container) with the drug must be separated from the contour packaging, gently shaken for 30 seconds and opened by turning the top. The contents of the ampoule (container) should be carefully squeezed into the nebulizer chamber according to the required dose (see table 2). The empty container should be thrown away, and the nebulizer chamber should be covered with a lid.
Benodil can be mixed with 0.9% saline.
Any unused suspension should be discarded immediately.
Children should use the drug under adult supervision.
Note: Important patient instructions:
You should carefully read the instructions for use given in the patient information leaflet included in the packaging of each nebulizer; Do not use ultrasonic nebulizers to administer Benodil, as they are incompatible with the drug; Rinse the mouth thoroughly with water after inhaling the prescribed dose to minimize the risk of oropharyngeal candidiasis; Rinse the face with water after using the respiratory mask to prevent skin irritation; The nebulizer should be properly washed and stored according to the manufacturer's instructions.
Children
Benodil should be used in children aged 6 months and older according to indications (see sections “Indications” and “Method of administration and dosage”).
Overdose
Benodil contains 0.1 mg/ml disodium edetate, which has been shown to cause bronchoconstriction at levels exceeding 1.2 mg/ml. Acute overdose of Benodil, even at excessive doses, is unlikely to be a clinically significant problem. Symptoms of acute intoxication with budesonide are unknown. In acute overdose, suppression of the hypothalamic-pituitary-adrenal axis may occur. In cases of chronic overdose, atrophy of the adrenal cortex may develop. Signs and symptoms of hypercorticism may occur. Stress adaptation disorders may also occur.
Overdose treatment
In case of chronic overdose, emergency treatment is not required. Continued inhalation therapy with Benodil in the recommended dose is accompanied by restoration of the function of the hypothalamic-pituitary-adrenal system within 1–2 days.
During stress, there may be a need for "corticosteroid protection" - additional administration of a high dose of hydrocortisone.
In the event of adrenal cortical atrophy, the patient should be classified as steroid-dependent and a maintenance dose of systemic corticosteroid should be prescribed.
Benodil contains 0.1 mg/ml of disodium edetate, which has been shown to cause bronchospasm at concentrations above 1.2 mg/ml.
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 (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000).
Table 3
Adverse reactions
| Organ system classes | Frequency | |
| Infections and infestations | Often | Oropharyngeal candidiasis Pneumonia (COPD patients) |
| On the part of the immune system | Rarely | Immediate and delayed hypersensitivity reactions*, including rash, contact dermatitis, urticaria, angioedema and anaphylactic reaction |
| From the endocrine system | Rarely | Signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation** |
| From the nervous system | Infrequently | Tremor Anxiety depression |
| Mental disorders | Rarely | Psychomotor hyperactivity Sleep disturbances Concern Aggression Behavioral changes (mostly in children) Increased nervous excitability |
| From the organs of vision | Infrequently | Cataract Blurred vision (see "Special warnings and precautions for use") |
| Unknown | Glaucoma Respiratory, thoracic and mediastinal disorders Cough |
| Often | Hoarseness Throat irritation |
| Rarely | Bronchospasm Dysphonia Hoarseness*** |
Skin and subcutaneous tissue disorders | Rarely | Bruises |
| From the musculoskeletal system | Infrequently | Muscle spasm |
* see below for description of individual adverse reactions; facial skin irritation.
** see the "Children" section below.
*** occasionally in children.
Description of selected adverse reactions
Oropharyngeal candidiasis is caused by exposure to drug residues. 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").
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 long 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
3 years.
Once opened, the container should be used within 12 hours. Any unused suspension should be discarded immediately.
Storage conditions
Store in original packaging at a temperature not exceeding 30 ° C. Keep out of the reach of children.
An opened container should be used within 12 hours.
Once the envelope is opened, the containers contained therein should be used within 3 months.
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
Production, packaging, batch control and batch release
Genetic S.p.A., Italy.
Secondary packaging and batch release
Pharmaceutical Plant "Polpharma" S.A., Poland.
Location of the manufacturer and its business address
Production, packaging, batch control and batch release
Canfora Quarter, 84084 Fisciano, Italy.
Secondary packaging and batch release
19 Pelplinski Street, 83-200, Starogard Gdański, Poland.
