Benodil

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BENO DIL (BENODIL)

Composition:

Active substance: budesonide;

1 ml of nebulizer suspension contains 0.25 mg or 0.5 mg of budesonide;

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

Pharmaceutical form. Nebulizer suspension.

Main physicochemical properties: homogeneous white-colored suspension.

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

Pharmacological Properties.

Pharmacodynamics.

Budesonide is a glucocorticosteroid with potent local anti-inflammatory activity, and the frequency and severity of its adverse effects 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, such as inhibition of mediator release in inflammation and suppression of cytokine-mediated immune responses, are likely to play an important role.

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

In a provocation study, four weeks of prior treatment with budesonide resulted in reduced bronchoconstriction in both immediate and late asthmatic reactions.

Onset of effect

After a single 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 the maximum effect might not be achieved until 4 weeks.

Airway responsiveness

Budesonide has also been shown to reduce airway hyperresponsiveness to histamine and methacholine in patients with hyperreactive airways.

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 generally transient reduction in growth velocity was observed, typically occurring during the first year of treatment. Limited long-term study data indicate that most children and adolescents treated with inhaled budesonide eventually achieve their expected adult height. However, in one study, children who received high-dose inhaled budesonide (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 who received budesonide in the form of an inhalation powder, a dose-dependent effect on plasma and urinary cortisol levels was observed. Budesonide in the form of an inhalation powder, when used at recommended doses, has significantly less effect on adrenal function than prednisone 10 mg, as confirmed by ACTH stimulation tests.

Children

Clinical use: bronchial asthma

The efficacy of budesonide in nebulized suspension form has been studied in numerous trials, which demonstrated its effectiveness in adults and children when administered once or twice daily for the preventive treatment of persistent bronchial asthma. Several representative studies are described below.

Clinical use: croup

Several studies in children with croup compared budesonide treatment with placebo. Representative studies evaluating budesonide for the treatment of croup in children are described 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 scores at 12 and 24 hours, and at 2 hours in patients with initial croup symptom scores above 3 points. Hospitalization duration was also reduced by 33%.

Efficacy in children with moderate to severe croup

To compare the efficacy of budesonide versus placebo, a randomized, double-blind, placebo-controlled study was conducted 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. Total croup symptom scores were assessed before dosing and at 0, 2, 6, 12, 24, 36, and 48 hours after the initial dose. At 2 hours, both budesonide and placebo groups showed similar improvement in croup symptom scores, with no statistically significant difference between groups. At 6 hours, the croup symptom score in the budesonide group was statistically significantly better than in the placebo group, and this improvement compared to placebo remained evident at 12 and 24 hours.

Pharmacokinetics.

Absorption

Systemic availability of budesonide in adults after administration of budesonide suspension via 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 swallowed drug. Maximum plasma concentration is reached approximately 10–30 minutes after the start of nebulization and is about 4 nmol/L after a 2 mg dose.

Distribution

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

Metabolism

Budesonide undergoes extensive (≈90%) first-pass metabolism in 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. Budesonide metabolism is primarily mediated by CYP3A enzymes of the cytochrome P450 subfamily.

Elimination

Budesonide metabolites are excreted mainly by the kidneys, either unchanged or in conjugated form. Unchanged budesonide is not detected in urine. In healthy adults, systemic clearance of budesonide is typically 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 also received 100 mg ketoconazole twice daily, plasma budesonide levels after oral administration (single 10 mg dose) increased on average by 7.8-fold. Data on similar interactions with inhaled budesonide are lacking, but a significant increase in plasma 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. In children with bronchial asthma, the terminal half-life of budesonide after inhalation is approximately 2.3 hours, which is similar to that observed in healthy adults. In patients aged 4–6 years with bronchial asthma, systemic availability of budesonide after administration of budesonide suspension via 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. Systemic availability in children is approximately half that in healthy 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 1 mg dose. Exposure parameters (Cmax and AUC) after a single 1 mg dose administered by nebulization in children aged 4–6 years are comparable to those in healthy adults receiving the same dose via the same nebulization system.

Clinical characteristics.

Indications.

Budesonide 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 inhaler devices is ineffective or inappropriate.

Budesonide 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 budesonide or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Budesonide is metabolized predominantly by CYP3A4. 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 (see sections "Special precautions for use" and "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 administration of these medicinal products should be as long as possible. Consideration may be given to reducing the dose of budesonide.

Limited data on similar interactions 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 by four times).

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.

Since adrenal function may be suppressed, an ACTH stimulation test intended for diagnosis of pituitary insufficiency may yield false results (low values).

Children

Interaction studies have been conducted only in adults.

Special precautions for use.

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

Patients without steroid dependence. 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, adequate treatment may be continued with Benodil as monotherapy.

Steroid-dependent patients. Transition from oral corticosteroids to Benodil may begin when the patient is in a relatively stable phase of the disease. For approximately 10 days, Benodil should be used in combination with the previously administered dose of oral corticosteroid.

Thereafter, the dose of oral corticosteroids should be gradually reduced (e.g., by 2.5 mg of prednisolone or equivalent per month) to the lowest possible level. In many cases, complete replacement of oral corticosteroids with Benodil is possible.

During transition from oral corticosteroid therapy to Benodil, 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 for these conditions should be initiated. Insufficient glucocorticoid therapy effect may be suspected if symptoms such as fatigue, headache, nausea, or vomiting occur, although this is rare. In such cases, temporary increase in the dose of oral glucocorticoids 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 initiated if necessary.

In patients who required emergency high-dose corticosteroid therapy or prolonged treatment with inhaled corticosteroids at the highest recommended dose, there is also a risk of adrenal gland dysfunction. Such patients may develop signs and symptoms of adrenal insufficiency 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 prolonged periods. 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, cataract, glaucoma, and less frequently, various psychiatric and behavioral disorders, including psychomotor hyperactivity, sleep disturbances, anxiety, depression, or aggression (particularly 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.

Benodil is not intended for rapid relief of acute episodes of bronchial asthma requiring short-acting inhaled bronchodilators. If treatment with short-acting bronchodilators is ineffective or if the patient requires more 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.

Impaired liver function may affect the elimination of glucocorticosteroids from the body, resulting in reduced 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 pre-systemic metabolism. The clinical significance of these changes for treatment with Benodil has not been fully established, as data on inhaled budesonide are lacking; however, increased plasma levels of the drug, and consequently increased risk of systemic adverse reactions, may 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 cannot be avoided, patients should be monitored for the development of systemic adverse effects associated with corticosteroid use. This has 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. Consideration should also be given to reducing the dose of budesonide (see section "Interaction with other medicinal products and other forms of interaction").

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

Oropharyngeal candidiasis may develop during treatment with inhaled corticosteroids. This infection may necessitate treatment with appropriate antifungal agents, and in some patients, discontinuation of therapy may be required (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 conclusive clinical data demonstrating differences between inhaled corticosteroid agents 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 may 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 a patient experiences symptoms such as blurred vision or other visual disturbances, ophthalmological consultation should be sought to evaluate possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy (CSCR), which has been reported after systemic or local corticosteroid use.

Children

Effect on growth

Regular monitoring of growth is recommended in children receiving long-term inhaled corticosteroid therapy. If growth velocity slows, therapy should be reviewed with the aim of reducing the inhaled corticosteroid dose to the lowest possible level at which effective control of bronchial asthma is maintained. The benefits of corticosteroid therapy should be carefully weighed against the potential risk of growth suppression. Additionally, referral to a pediatric pulmonologist is important.

Use during pregnancy or breastfeeding.

Pregnancy

Most findings from prospective epidemiological studies and international post-marketing experience indicate that inhaled budesonide treatment during pregnancy does not adversely affect fetal/neonatal health.

Animal studies have demonstrated that glucocorticosteroids may cause developmental abnormalities. However, these data are not considered relevant to 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 treatment is maintained during pregnancy. As with any medicinal product 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 less pronounced systemic effects when doses required for equivalent respiratory response are used.

Breastfeeding period

Budesonide passes into breast milk. However, when therapeutic doses of Benodil are used, no effect on the breastfed infant is expected. Benodil may be used during breastfeeding.

Maintenance treatment with inhaled budesonide (200 or 400 mcg twice daily) in breastfeeding women with bronchial asthma results in only minimal systemic exposure to 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 concentration in all infant plasma samples was below the limit of quantification.

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

The medication is intended for administration by nebulization using a compressor-type nebulizer (see below).

Dosing

The dosage of Benodil should be adjusted according to individual patient needs. The dose should be reduced to the lowest level required to maintain adequate control of bronchial asthma.

For patients in whom an increased therapeutic effect is desired, particularly those without excessive mucus in the airways, increasing the dose of Benodil is recommended instead of combined treatment with oral corticosteroids, as this is associated with a lower risk of systemic adverse effects.

Bronchial Asthma

Initiation of Therapy

At the beginning of treatment, during periods of exacerbation of bronchial asthma, and when reducing or discontinuing oral glucocorticoid therapy, the recommended dose of Benodil is as specified in Table 1.

Maintenance Therapy

The maintenance dose should be individually adjusted and should be the lowest dose at which the patient remains free of disease symptoms.

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.

Table 1

	Initial dose	Maintenance 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 older Adults (including elderly patients)	1–2 mg twice daily	0.5–1 mg twice daily	4 mg

Patients who are receiving oral glucocorticoids as maintenance therapy

Becloforte allows discontinuation or significant reduction of oral glucocorticoid dosage while maintaining control of bronchial asthma. To initiate the transition from oral steroids, the patient should be in a relatively stable condition. For approximately 10 days, administer a high dose of Becloforte in combination with the previously used dose of oral steroid. After this period, 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, oral steroid therapy can be completely discontinued and replaced with Becloforte. For further details on withdrawal of oral glucocorticoids, see section "Special Instructions".

Dosage specifics

Becloforte can be mixed with 0.9% physiological saline. The mixture should be used within 30 minutes.

Table 2

Correspondence between volume (ml) and dose (mg) of Becloforte preparation

Dose	Volume of the medicinal product Benodil, nebulizer suspensions at 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 administered as a single administration or as two administrations of 1 mg each, with a 30-minute interval between doses. The administration may be repeated every 12 hours, up to a maximum of 36 hours or until clinical improvement occurs.

Method of administration

For inhalation, Benodil requires a nebulizer connected to a compressor (compressor type). Not all nebulizer and compressor models are suitable for administering Benodil. To ensure optimal delivery of budesonide, the compressor must provide an adequate airflow (5–8 L/min), and the nebulizer chamber volume should be 2–6 mL.

For pediatric use, a face mask of appropriate size with a good fit and tight seal to the face is recommended.

The duration of inhalation and the delivered dose depend on the breathing pattern and the amount of medication placed in the nebulizer.

The ampoule (container) must be detached from the blister pack, gently shaken for 30 seconds, and opened by twisting the top part. 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 discarded, and the nebulizer chamber covered with its cap.

Benodil may be mixed with 0.9% saline solution.

Unused suspension should be discarded immediately.

Benodil should be administered to children under adult supervision.

Note. Important instructions for the patient:

• carefully read the instructions for use provided in the patient information leaflet included in the packaging of each nebulizer;
• do not use ultrasonic nebulizers for administering Benodil, as they are incompatible with the medicinal product;
• thoroughly rinse the mouth with water after inhalation of the prescribed dose to minimize the risk of developing oropharyngeal candidiasis;
• rinse the facial skin with water after using the face mask to prevent skin irritation;
• properly clean and store the nebulizer according to the manufacturer's instructions.

Children.

Benodil may be used in children aged 6 months and older, as indicated (see sections "Indications" and "Method of administration and dosage").

Overdose.

Benodil contains 0.1 mg/mL of edetate disodium, which has been shown to cause bronchoconstriction if its concentration exceeds 1.2 mg/mL. Acute overdose of Benodil, even with administration of excessive doses, is unlikely to result in clinically significant problems.

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 3 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, angioneurotic edema, and anaphylactic reaction
Endocrine disorders	Uncommon	Signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation **
Psychiatric disorders	Uncommon	Anxiety, depression
	Uncommon	Psychomotor hyperactivity, sleep disorders, aggression, behavioral changes (mainly in children)
Nervous system disorders	Uncommon	Tremor***
Eye disorders	Uncommon	Cataract, blurred vision (see also "Special precautions for use")
	Not known	Glaucoma
Respiratory, thoracic and mediastinal disorders	Common	Cough, throat irritation, hoarseness
	Uncommon	Bronchospasm, dysphonia, hoarseness****
Skin and subcutaneous tissue disorders	Uncommon	Contusion
Musculoskeletal and connective tissue disorders	Uncommon	Muscle spasms

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

** See section "Children" below.

*** Based on frequency recorded 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 medicinal product. 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").

Sometimes, when a nebulizer with a face mask was used, hypersensitivity reactions in the form of facial skin irritation have been reported. To prevent irritation, the face should be washed after using the mask.

In placebo-controlled studies, cataract was reported as an uncommon adverse effect in the placebo group.

In pooled clinical trials involving 13,119 patients treated with inhaled budesonide and 7,278 patients receiving placebo, the frequency of anxiety was 0.52% for inhaled budesonide and 0.63% for placebo. The frequency of depression was 0.67% for inhaled budesonide and 1.15% for placebo.

Children

Due to the risk of growth retardation in children, regular monitoring of growth parameters should be performed (see section "Special precautions").

Reporting suspected adverse reactions.

Reporting of adverse reactions after medicinal product authorization is important. It allows ongoing monitoring of the benefit-risk balance of this 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 the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

An opened container should be used within 12 hours. Unused suspension should be discarded immediately.

Storage conditions.

Store in the 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.

After opening the pouch, 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 pouch; 4 pouches in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

1. Manufacturing, packaging, batch control and batch release

Djenetik S.p.A., Italy /
Genetic S.p.A., Italy.

2. Secondary packaging and batch release

Pharmaceutical Works "Polpharma" S.A., Poland /
Pharmaceutical Works "Polpharma" S.A., Poland.

Manufacturer's location and address of place of business.

1. Manufacturing, packaging, batch control and batch release

Contrada Canfora, 84084 Fisciano, Italy /
Contrada Canfora, Fisciano, 84084, Italy.

2. Secondary packaging and batch release

19, Pelplinska Str., 83-200 Starogard Gdanski, Poland /
19, Pelplinska Str., 83-200 Starogard Gdanski, Poland.