Budesonide-intelii neb

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BUDENOSIDE-INTELI NEB

Composition:

Active substance: budesonide; 0.25 mg/mL or 0.5 mg/mL;

1 single-dose container contains 0.5 mg or 1 mg of budesonide;

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

Pharmaceutical form. Suspension for nebulization.

Main physico-chemical properties: white homogeneous suspension.

Pharmacotherapeutic group. Inhalation agents used in the treatment of obstructive respiratory diseases. Glucocorticoids. ATC code R03BA02.

Pharmacological properties.

Pharmacodynamics.

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

Local anti-inflammatory effect

The precise mechanism of action of glucocorticosteroids in the treatment of bronchial asthma has not been fully elucidated. Anti-inflammatory effects are likely to play an important role, such as inhibition of inflammatory mediator release and suppression of cytokine-mediated immune response.

A clinical study in patients with bronchial asthma comparing inhaled and oral formulations of budesonide at doses calculated to achieve similar systemic bioavailability demonstrated a statistically significant advantage in efficacy of inhaled budesonide, as compared to oral budesonide, relative to placebo. Thus, the therapeutic effect of standard doses of inhaled budesonide may largely be explained by direct action on the airways.

In a provocation study, pretreatment with budesonide for four weeks resulted in reduced bronchoconstriction in both immediate and late-type asthmatic reactions.

Onset of effect

After a single oral inhalation of budesonide via a dry powder inhaler, improvement in lung function occurs within several hours. With therapeutic use of budesonide inhalations via a dry powder inhaler, improvement in lung function was observed within 2 days of starting treatment, although maximum effect might not be achieved until 4 weeks.

Airway reactivity

It has also been demonstrated that budesonide reduces airway hyperresponsiveness to histamine and methacholine in patients with hyperreactivity.

Exercise-induced bronchial asthma

Inhaled budesonide therapy has been effectively used for the prevention of exercise-induced asthma attacks.

Growth

In short-term studies, a small and usually transient reduction in growth velocity was observed, typically occurring during the first year of treatment. Limited long-term data suggest that most children and adolescents receiving inhaled budesonide therapy eventually achieve their expected adult height. However, in one study, children who received inhaled budesonide at high doses (400 mcg daily) via a dry powder inhaler for 6 years without dose titration to the lowest effective dose were on average 1.2 cm shorter in adulthood compared to those who received placebo over a similar period. For information on dose titration to the lowest effective dose and monitoring of growth in children, see section "Special precautions for use".

Effect on plasma cortisol concentration

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

Children

Clinical use: bronchial asthma

The efficacy of budesonide has been studied in numerous trials, which demonstrated the effectiveness of the drug in adults and children administered once or twice daily for prophylactic treatment of persistent asthma. Representative examples of such studies are provided below.

Clinical use: croup

Several studies in children with croup compared budesonide treatment with placebo. Examples of representative studies on the use of budesonide in children with croup are provided below.

Efficacy in children with mild to moderate croup

To determine whether budesonide improves croup symptom scores and reduces hospitalization duration, a randomized, double-blind, placebo-controlled study was conducted in 87 children (aged 7 months to 9 years) hospitalized with a clinical diagnosis of croup. Participants received an initial dose of budesonide (2 mg) or placebo, followed by doses of budesonide 1 mg or placebo every 12 hours. Statistically, budesonide significantly improved croup symptom scores at 12 and 24 hours, and at 2 hours in patients with initial symptom scores above 3 points. Hospitalization duration was also reduced by 33%.

Efficacy in children with moderate to severe croup

In a randomized, double-blind, placebo-controlled study, the efficacy of budesonide versus placebo in the treatment of croup was compared 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. Croup symptom scores were assessed at 0, 2, 6, 12, 24, 36, and 48 hours after the initial dose. At 2 hours, patients in both budesonide and placebo groups showed similar improvement in croup symptom scores; no statistically significant difference was observed. At 6 hours, croup symptom scores in the budesonide group improved significantly compared to placebo; this improvement was maintained at 12 and 24 hours.

Pharmacokinetics.

Absorption

Systemic availability of budesonide after administration as a nebulized suspension via a jet nebulizer is approximately 15% of the nominal dose and 40–70% of the dose delivered to the patient. A minor portion of this amount is due to systemic absorption of the drug that has been swallowed. Maximum plasma concentration is reached approximately 10–30 minutes after the start of nebulization and is about 4 nmol/L following a 2 mg dose.

Distribution

The volume of distribution of budesonide is approximately 3 L/kg. Plasma protein binding is on average 85–90%.

Metabolism

Budesonide undergoes extensive first-pass metabolism in the liver (≈90%) into 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. Budesonide metabolism is primarily mediated by CYP3A4, a member of the cytochrome P450 subfamily.

Elimination

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

Linearity

Budesonide kinetics are dose-proportional when administered at clinically relevant doses.

In a study where patients received 100 mg ketoconazole twice daily concomitantly with a single 10 mg oral dose of budesonide, plasma levels of the latter increased on average by 7.8-fold. Data on similar interactions with inhaled budesonide are lacking, but a significant increase in plasma drug levels is entirely expected.

Children

In children aged 4–6 years with bronchial asthma, systemic clearance of budesonide is approximately 0.5 L/min. Clearance in children (per kg body weight) is about 50% higher than in adults. The terminal half-life of budesonide in children with bronchial asthma after inhalation is approximately 2.3 hours, a value similar to that observed in healthy volunteers. After administration of budesonide via jet nebulizer, systemic availability 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. Systemic availability in children is approximately half that in adults.

In children aged 4–6 years with bronchial asthma, maximum plasma concentration is reached within 20 minutes after the start of nebulization and is approximately 2.4 nmol/L after a single 1 mg dose. Exposure parameters of budesonide (Cmax and AUC) after a single 1 mg nebulized dose in children aged 4–6 years are comparable to those in healthy adult volunteers receiving budesonide at the same dose via the same nebulization system.

Clinical characteristics.

Indications.

The medicinal product contains a potent non-halogenated corticosteroid – budesonide, intended for the treatment of bronchial asthma in patients in whom administration via pressurized metered dose inhalers or dry powder inhalers is ineffective or inappropriate.

BODESONIDE-INTELI NEB is also recommended for use in infants and children with croup (a complication of acute viral infection of the upper respiratory tract, also known as laryngotracheobronchitis or subglottic laryngitis) requiring hospitalization.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Metabolism of budesonide occurs predominantly via CYP3A4. Concomitant administration with CYP3A inhibitors, such as itraconazole, ketoconazole, HIV protease inhibitors, and products containing cobicistat, is expected to increase the risk of systemic corticosteroid side effects (see section "Special precautions for use" and section "Pharmacological properties").

Combination of budesonide with strong CYP3A inhibitors should be avoided, except when the benefit outweighs the increased risk of systemic corticosteroid-related adverse effects; if such combination cannot be avoided, patients should be monitored for the occurrence of systemic corticosteroid-related adverse effects. When budesonide is used concomitantly with antifungal agents (such as itraconazole and ketoconazole), the interval between administrations of these medicinal products should be as long as possible. Consideration may be given to reducing the dose of budesonide.

Limited data on this interaction with high doses of inhaled budesonide show that co-administration of itraconazole 200 mg once daily increases plasma concentrations of inhaled budesonide (single dose 1000 mcg) significantly (on average, 4-fold).

In women concurrently using estrogens or hormonal contraceptives, plasma concentrations of budesonide were increased and corticosteroid effects were enhanced; however, this effect was not observed when budesonide was used together with low-dose combined oral contraceptives.

Due to possible suppression of adrenal function, an ACTH stimulation test for diagnosing pituitary insufficiency may yield false-negative results (low values).

Children

Interaction studies have been conducted only in adult patients.

Special precautions for use.

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

Patients not dependent on steroids. Therapeutic effect is usually achieved within 10 days. In patients with excessive mucus secretion in the bronchi, a short-term (approximately 2 weeks) additional course of oral corticosteroids may be initially administered. After completion of oral corticosteroid therapy, treatment with budesonide as monotherapy may be sufficient.

Patients dependent on steroids. Transition from oral corticosteroids to budesonide may begin when the patient is in a relatively stable phase of the disease. In such cases, Budesonide-Inteli Neb should be used in combination with the previously administered dose of oral corticosteroid for approximately 10 days.

After this period, the dose of oral corticosteroids should be gradually reduced (e.g., by 2.5 mg of prednisolone or equivalent per month) until the lowest possible dose is reached. In many cases, complete replacement of oral corticosteroids with budesonide is possible.

During transition from oral corticosteroid therapy to budesonide, a reduction in systemic corticosteroid effects is usually observed, which may lead to the emergence of allergy or arthritis symptoms such as rhinitis, eczema, and musculoskeletal pain. Specific treatment should be initiated for these conditions. In rare cases, symptoms such as fatigue, headache, nausea, and vomiting may occur, indicating systemic glucocorticoid insufficiency. In such cases, temporary dose increase of the oral corticosteroid may sometimes be required.

As with other forms of inhaled therapy, paradoxical bronchospasm may occur, characterized by increased wheezing immediately after administration. If this occurs, inhaled budesonide treatment should be discontinued immediately, the patient's condition should be assessed, and alternative therapy should be initiated if necessary.

In patients who required emergency high-dose corticosteroid therapy or long-term treatment with inhaled corticosteroids at the highest recommended dose, there is also a risk of developing adrenal gland dysfunction. In these patients, symptoms of adrenal insufficiency may occur during periods of severe stress. Additional systemic corticosteroid therapy may be prescribed during stressful situations or prior to planned surgical procedures.

Systemic effects may occur with the use of any inhaled corticosteroid, especially when high doses are administered over a prolonged period. The likelihood of such effects is significantly lower with inhaled corticosteroids compared to 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. Rarely, various psychiatric and behavioral disorders may occur, including psychomotor hyperactivity, sleep disturbances, anxiety, depression, or aggression (particularly in children). Therefore, it is important to titrate the dose of inhaled corticosteroids to the lowest effective dose that maintains adequate control of bronchial asthma.

Budesonide is not intended for rapid relief of acute episodes of bronchial asthma requiring the use of short-acting inhaled bronchodilators. If treatment with short-acting bronchodilators is ineffective or if the patient requires more frequent inhalations than usual, medical intervention is necessary. In such cases, intensification of the usual therapy should be considered, for example, by increasing the dose of inhaled budesonide, adding a long-acting beta-agonist, or initiating a course of oral glucocorticosteroids.

Reduced liver function may affect the elimination of glucocorticosteroids from the body due to decreased clearance and increased systemic exposure. The potential for adverse effects should therefore be considered.

However, plasma clearance after intravenous administration of budesonide was similar in patients with liver cirrhosis and healthy volunteers. After oral administration, systemic bioavailability of budesonide increased due to impaired liver function, resulting from reduced presystemic metabolism. The clinical significance of these changes for budesonide treatment has not been fully established, as data on inhaled budesonide are lacking; however, increased plasma levels of the drug—and consequently an increased risk of systemic adverse reactions—can be expected.

Concomitant use with CYP3A inhibitors, such as itraconazole, ketoconazole, HIV protease inhibitors, and products containing cobicistat, is expected to increase the risk of systemic corticosteroid side effects. Such combinations should be avoided unless the benefit outweighs the increased risk. If such combination therapy cannot be avoided, patients should be monitored for systemic adverse effects associated with corticosteroid use. This is of limited clinical significance during short-term (1–2 weeks) treatment with itraconazole, ketoconazole, or other potent CYP3A inhibitors, but should be considered during long-term therapy. A reduction in the budesonide dose should also be considered (see section "Interaction with other medicinal products and other forms of interaction").

The nebulizer chamber and mouthpiece or face mask should be washed with hot water and mild detergent after each use. The nebulizer chamber should be thoroughly rinsed and dried by connecting it to the compressor or air receiver.

Oral candidiasis may develop during treatment with inhaled corticosteroids. This infection may require treatment with appropriate antifungal agents, and in some patients, discontinuation of therapy may be necessary (see also section "Method of administration and dosage").

Pneumonia in patients with COPD

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

Evidence suggests an increased risk of pneumonia with higher corticosteroid doses, although this has not been definitively demonstrated in any study.

There are no comprehensive clinical data demonstrating differences between inhaled corticosteroid products in the magnitude of pneumonia risk.

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

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

Visual disturbances

Visual disturbances may occur with systemic and local use of corticosteroids. If patients experience symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist to evaluate possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy (CSC), which has been reported after systemic or local corticosteroid use.

Children

Effect on growth

Regular growth monitoring is recommended in children receiving long-term treatment with inhaled corticosteroids. If growth retardation occurs, therapy should be re-evaluated with the aim of reducing the inhaled corticosteroid dose to the lowest possible level that maintains effective control of bronchial asthma. The benefits of corticosteroid therapy should be carefully weighed against the potential risk of growth suppression. Additionally, referral to a pediatric pulmonologist should be considered.

Use during pregnancy or breastfeeding.

Pregnancy

Results from a large prospective epidemiological study and post-marketing experience indicate that treatment with inhaled budesonide during pregnancy does not lead to adverse effects on the fetus or newborn.

Animal studies have demonstrated that glucocorticosteroids can cause developmental abnormalities. However, these findings are not considered clinically relevant in humans when recommended doses are used. Nevertheless, inhaled budesonide therapy should be regularly reviewed and administered at the lowest effective dose. It is important for both the fetus and the pregnant woman that adequate asthma control is maintained during pregnancy. As with other medicinal products used during pregnancy, the benefit of budesonide use for the mother should be weighed against potential risks to the fetus.

Inhaled glucocorticosteroids should be preferred over oral glucocorticosteroids due to their lower systemic effects when equivalent respiratory responses are achieved.

Breastfeeding

Budesonide passes into breast milk. However, no adverse effects on the breastfed infant are expected with therapeutic doses of budesonide. Budesonide-Inteli Neb can be used during breastfeeding.

Maintenance treatment with inhaled budesonide (200 or 400 µg twice daily) in breastfeeding women with bronchial asthma results in only minimal systemic exposure of budesonide in breastfed infants.

In a pharmacokinetic study, the calculated daily dose in breastfed infants was 0.3% of the mother’s daily dose for both dose levels, and the average plasma concentration in breastfed infants was estimated to be one six-hundredth of the concentration observed in maternal plasma, assuming complete oral bioavailability in the infant. Budesonide concentrations in all infant plasma samples were below the limit of quantification.

Considering available data on inhaled budesonide and the fact that budesonide exhibits linear pharmacokinetic properties within therapeutic dose ranges after nasal, inhaled, oral, or rectal administration, exposure to budesonide in breastfed infants is expected to be low when used at therapeutic doses.

Ability to influence reaction speed when driving vehicles or operating machinery.

Budesonide has no effect or has a negligible effect on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Dosing

The dosage of the drug BUDENONIDE-INTELI NEB must be adjusted according to individual patient needs.

Dosing Schemes

The dose delivered to the patient depends on the nebulizing equipment used. Nebulization time and delivered dose depend on the airflow rate, nebulizer chamber volume, and fill volume. The airflow rate through the nebulizing device 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) should be prescribed to children under 12 years of age only in cases of severe asthma and for a limited period of time.

Bronchial Asthma

Initiation of Therapy

At the beginning of treatment, during exacerbations of bronchial asthma, and when reducing or discontinuing oral glucocorticosteroids, the recommended dosage is:

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

Children aged 12 years and older: dosage is the same as for adults.

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

Maintenance Therapy

The maintenance dose should be individually adjusted and should be the lowest dose at which the patient remains asymptomatic.

Adults (including elderly patients) and children aged 12 years and older: 0.5–1 mg twice daily.

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

Patients on Oral Glucocorticosteroids for Maintenance Therapy

BUDENONIDE-INTELI NEB allows for discontinuation or significant reduction of oral glucocorticosteroid dosage while maintaining control of bronchial asthma. The transition from oral steroids should begin when the patient is in a relatively stable condition. For approximately 10 days, a high dose of budesonide in nebulized form should be administered in combination with the previously used dose of oral steroid. After this period, the oral steroid dose should be gradually reduced to the lowest possible level, for example by 2.5 mg of prednisolone or equivalent per month. Often, oral steroid therapy can be completely discontinued and replaced with BUDENONIDE-INTELI NEB. For further details on withdrawal of oral glucocorticosteroids, see section "Special Precautions for Use".

Dose Splitting and Mixing with Other Medicinal Products

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

Table 1

DOSAGE RECOMMENDATIONS

Dose (mg)	Volume of the medicinal product BUDENOSIDE-INTELI NEB, suspension for nebulization
	0.25 mg/ml	0.5 mg/ml
0.25	1 ml	-
0.5	2 ml	1 ml
0.75	3 ml	-
1.0	4 ml	2 ml
1.5	6 ml	3 ml
2.0	8 ml	4 ml

For patients in whom an enhanced therapeutic effect is desirable, especially those without excessive mucus in the airways, increasing the dose of budesonide is recommended instead of combination therapy with oral corticosteroids, due to a lower risk of systemic adverse effects.

Croup

For infants and children with croup, the usual dose is 2 mg of nebulized budesonide. This dose should be administered as a single dose or divided into two doses of 1 mg each, given 30 minutes apart. Administration may be repeated every 12 hours, up to a maximum of 36 hours or until clinical improvement occurs.

Method of administration

Budesonide-Intelii Neb shall be used only with appropriate nebulizers.

Instructions for correct use of the medicinal product

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

Budesonide-Intelii Neb should be administered using a jet nebulizer with a mouthpiece or a suitable face mask. The nebulizer should be connected to an air compressor providing an adequate airflow (6–8 L/min), and the filling volume should be 2–4 mL.

Note. It is important that the patient:

• carefully reads the instructions for use provided in the patient information leaflet included in the packaging of each nebulizer;
• understands that ultrasonic nebulizers are unsuitable for administration of Budesonide-Intelii Neb and therefore their use is not recommended;
• is informed about the possibility of mixing Budesonide-Intelii Neb with 0.9% sodium chloride solution and with nebulizing solutions containing terbutaline, salbutamol, fenoterol, acetylcysteine, sodium cromoglicate, or ipratropium bromide, and knows that the mixture must be used within 30 minutes;
• rinses the mouth with water after inhalation of the prescribed dose to minimize the risk of oropharyngeal candidiasis;
• washes the facial skin with water after using a face mask to prevent skin irritation;
• properly cleans and stores the nebulizer according to the manufacturer’s instructions.

Children

Budesonide-Intelii Neb may be used in children as indicated (see sections "Indications" and "Dosage and administration").

Overdose

Budesonide-Intelii Neb contains 0.1 mg/mL of disodium edetate, which has been shown to cause bronchoconstriction if its concentration exceeds 1.2 mg/mL. Acute overdose of budesonide, even with excessive doses, is unlikely to present a clinically significant problem.

Adverse reactions.

The following definitions were used to assess the frequency of adverse effects. Frequency is defined as follows: very common (≥1/10); common (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10000 to <1/1000); very rare (<1/10000).

Table 2

Adverse reactions classified by system organ classes and frequency

System organ classes	Frequency	Adverse reactions
Infections and infestations	Common	Oropharyngeal candidiasis Pneumonia (in patients with COPD)
Immune system disorders	Uncommon	Immediate and delayed hypersensitivity reactions*, including rash, contact dermatitis, urticaria, angioedema and anaphylactic reaction
Endocrine disorders	Uncommon	Signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation**
Gastrointestinal disorders	Common	Nausea
Psychiatric disorders	Uncommon	Anxiety Depression
	Uncommon	Psychomotor hyperactivity Sleep disorders Aggression Behaviour changes (mainly in children)
Nervous system disorders	Uncommon	Tremor***
Eye disorders	Uncommon	Cataract
	Not known	Glaucoma Blurred vision (see also section "Special warnings and precautions for use")
Respiratory, thoracic and mediastinal disorders	Common	Cough
		Hoarseness
		Throat irritation
	Uncommon	Bronchospasm
		Dysphonia
		Hoarseness****
Skin and subcutaneous tissue disorders	Uncommon	Contusion
Musculoskeletal and connective tissue disorders	Uncommon	Muscle cramps

* see description of individual adverse reactions below; facial skin irritation

** see section "Children" below

*** based on frequency observed during clinical trials

**** rarely in children.

Sometimes, when using inhaled glucocorticosteroids, signs or symptoms of systemic glucocorticosteroid side effects may occur, likely depending on dose, duration of exposure, concomitant and prior corticosteroid exposure, as well as individual sensitivity (see section "Special precautions").

Description of individual adverse reactions

Oropharyngeal candidiasis occurs due to deposition of the drug. Patients should be instructed to rinse the mouth with water after each inhalation of the maintenance dose to minimize this risk.

As with any inhaled therapy, paradoxical bronchospasm may very rarely occur (see section "Special precautions").

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

Cataract has also been infrequently reported in the placebo group in placebo-controlled studies.

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

Children

Due to the risk of growth suppression in children, growth monitoring should be performed in these patients as described in the section "Special precautions".

Reporting of adverse reactions

Reporting adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

After opening the envelope, the containers inside should be used within 3 months. After this period, any remaining medication must be discarded. The contents of an opened container should be used within 12 hours. After this period, any remaining medication must be discarded.

Storage conditions.

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

Packaging.

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

Prescription category.

Prescription only.

Manufacturer.

GENETIC S.P.A.

Manufacturer's location and address of its business site.

CONTRADA CANFORA, FISCIANO, 84084, Italy