Budesonide-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Budesonide-Teva (Budesonide-Teva)

Composition:

Active substance: budesonide;

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

Excipients: polysorbate 80; sodium chloride; sodium citrate dihydrate; citric acid monohydrate; disodium edetate dihydrate; water for injections.

Pharmaceutical form. Nebulizer suspension.

Main physicochemical properties: white to almost white suspension in a single-dose ampoule.

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

Pharmacological Properties.

Pharmacodynamics.

Budesonide is a non-halogenated glucocorticoid with potent local anti-inflammatory action and a lower frequency and severity of adverse effects compared to oral corticosteroids.

The precise mechanism of action of glucocorticoids in the treatment of bronchial asthma has not been fully elucidated. It is likely that anti-inflammatory effects (particularly on T-lymphocytes, eosinophils, and mast cells), such as suppression of inflammatory mediator release and inhibition of cytokine-mediated immune responses, play an important role.

A clinical study involving patients with bronchial asthma, comparing inhaled and oral formulations of budesonide at doses calculated to achieve similar systemic bioavailability, demonstrated a statistically significant efficacy advantage of inhaled budesonide over placebo; the oral formulation of budesonide did not show such an advantage. Thus, the therapeutic effect of standard doses of inhaled budesonide is largely attributable to its direct action on the airways.

In a provocation study, pretreatment with budesonide for 4 weeks resulted in anti-anaphylactic and anti-inflammatory effects, manifested as reduced bronchial obstruction in both immediate and delayed-type allergic reactions.

Onset of Effect

Improvement in lung function occurs within several hours after a single oral inhalation of budesonide using a dry powder inhaler. Studies have shown that improvement in lung function occurs within 2 days of initiating therapy with inhaled budesonide via a dry powder inhaler, although maximal effect may not be achieved until 4 weeks.

Airway Reactivity

It has also been established that budesonide reduces airway hyperresponsiveness to histamine and methacholine in patients with hyperreactive airways.

Exercise-induced Bronchial Asthma

Inhaled budesonide therapy has been used effectively to prevent asthma attacks triggered by physical exertion.

Effect on Plasma Cortisol Concentration

In studies involving healthy volunteers, budesonide demonstrated a dose-dependent effect on plasma and urinary cortisol levels. When used at recommended doses, the drug has significantly less impact on adrenal function than prednisone 10 mg, as confirmed by ACTH stimulation tests.

Effect on Growth

In short-term studies, a slight, usually transient reduction in growth velocity was observed, primarily during the first year of treatment. Limited long-term data suggest that most children and adolescents receiving 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 than those who received placebo over a similar period. For information on dose titration and growth monitoring in children, see the section "Special Warnings and Precautions for Use."

Clinical Use: Bronchial Asthma

The efficacy of the drug has been studied in numerous trials, which demonstrated its effectiveness in adults and children when administered 1–2 times daily for prophylactic treatment of persistent asthma.

Clinical Use: Croup

Several studies in children with croup compared budesonide treatment with placebo. Representative studies evaluating the use of budesonide, nebulized suspension, 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. Study participants received an initial dose of budesonide (2 mg) or placebo, followed by budesonide 1 mg or placebo every 12 hours. Statistically significant improvement in croup severity scores was observed with budesonide at 12 and 24 hours, and at 2 hours in patients with an initial croup severity score above 3 points. A 33% reduction in hospitalization duration was observed.

Efficacy in Children with Moderate to Severe Croup

In a randomized, double-blind, placebo-controlled study, the efficacy of budesonide nebulized suspension versus placebo was evaluated in 83 children (aged 6 months to 8 years) hospitalized with croup. Patients received 2 mg budesonide 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, similar improvement in croup symptom scores was observed in both the budesonide and placebo groups, with no statistically significant difference. At 6 hours, the croup symptom score in the budesonide group was statistically significantly better than in the placebo group, and this improvement remained evident at 12 and 24 hours.

Pharmacokinetics.

Absorption

Systemic availability of budesonide after administration of 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 drug swallowed. Maximum plasma concentration (C_max) 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

Approximately 90% of budesonide is metabolized during first-pass metabolism in the liver via CYP3A4 into metabolites with low glucocorticoid activity. The glucocorticoid activity of the main metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. Budesonide metabolism occurs predominantly via CYP3A enzymes of the cytochrome P450 subfamily.

Elimination

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

Linearity

The pharmacokinetic parameters of budesonide are dose-proportional when administered at clinically relevant doses.

In a study where patients also received 100 mg ketoconazole twice daily, plasma levels of budesonide 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 of the drug is entirely expected.

Children

In children aged 4–6 years with bronchial asthma, systemic clearance of budesonide is approximately 0.5 L/min. On a body weight basis, clearance in children 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, nearly identical to that in healthy adult volunteers.

In children aged 4–6 years with bronchial asthma, systemic bioavailability of budesonide after administration of nebulized suspension via a jet nebulizer (Pari LC Jet Plus® with Pari Master® compressor) is approximately 6% of the nominal dose and 26% of the delivered dose. Systemic availability in children is approximately half that in healthy adult volunteers.

In children aged 4–6 years with bronchial asthma, C_max is reached within 20 minutes after starting nebulization of 1 mg budesonide and is approximately 2.4 nmol/L. Budesonide exposure parameters (C_max and AUC) after a single 1 mg dose administered via nebulization in children aged 4–6 years are comparable to those in healthy adult volunteers receiving the same dose via the same nebulization system.

Clinical characteristics.

Indications.

The medicinal product Budesonide-Teva is indicated for the treatment of bronchial asthma in patients in whom administration via pressurized metered-dose inhalers or dry powder inhalers is ineffective or inappropriate.

Budesonide-Teva 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. Therefore, concomitant use with CYP3A4 inhibitors such as ketoconazole, itraconazole, HIV protease inhibitors (e.g., ritonavir, saquinavir), and medicinal products containing cobicistat increases the risk of systemic exposure to budesonide (see section "Special warnings and precautions for use").

Concomitant use of such combinations should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side effects; in such cases, patients should be monitored for signs of systemic corticosteroid adverse effects. When budesonide is used concomitantly with antifungal medicinal products (e.g., itraconazole, ketoconazole), the interval between administrations 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 the plasma concentration of inhaled budesonide (single dose 1000 mcg) significantly (on average by 4 times).

In women taking estrogens or hormonal contraceptives, plasma concentrations of budesonide may be increased and corticosteroid effects 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 the diagnosis of hypopituitarism may yield false-negative results (low values).

Children. Interaction studies have only been conducted in adults.

Special precautions for use.

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

Non-steroid-dependent patients. Therapeutic effect is usually achieved within 10 days. Patients with excessive mucus secretion in the bronchi may initially require short-term therapy with oral corticosteroids (approximately 2 weeks). After a course of oral corticosteroids, treatment with budesonide alone may be sufficient.

Steroid-dependent patients. Transitioning patients receiving oral corticosteroids to inhaled corticosteroids and their further management should be performed with particular caution when the patient is in a relatively stable phase of the disease. In such cases, the medicinal product Budesonide-Teva should be administered in combination with the previously used 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) to the lowest possible dose. Complete replacement of oral corticosteroid with an inhaled corticosteroid medicinal product may be possible.

During transition from oral corticosteroid therapy to inhaled budesonide, symptoms previously suppressed by systemic glucocorticoid action may appear, such as allergy or arthritis symptoms including rhinitis, eczema, and musculoskeletal pain. Specific therapy should be initiated to treat these conditions. 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, treatment with inhaled budesonide 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 long-term 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 corticosteroids should be considered during periods of stress or prior to scheduled surgical procedures.

Systemic effects may occur with any inhaled corticosteroid, especially when high doses are used 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, and glaucoma, and less frequently, a range of psychological and behavioral disorders such as psychomotor hyperactivity, sleep disturbances, anxiety, depression, or aggression (particularly in children). Therefore, the dose of inhaled corticosteroids should be titrated to the lowest effective dose that maintains adequate control of bronchial asthma.

The medicinal product is not intended for the treatment of acute episodes of bronchial asthma requiring short-acting inhaled bronchodilators. If treatment with short-acting bronchodilators is ineffective or if patients require more inhalations than usual, medical intervention is necessary. In such situations, intensification of 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 glucocorticoids.

Liver dysfunction may affect the elimination of glucocorticosteroids from the body, as clearance is reduced and systemic exposure increases. The possibility of adverse effects should be kept in mind. 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 inhaled budesonide therapy has not been fully established due to lack of data on inhaled budesonide, but increased plasma levels of the drug, and thus increased risk of systemic adverse reactions, can be expected.

Concomitant use with strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, HIV protease inhibitors, and products containing cobicistat, is expected to increase the risk of systemic exposure. Such combinations should be avoided unless the benefit outweighs the increased risk; in such cases, patients should be monitored for systemic adverse effects associated with corticosteroid use. This has limited clinical significance during short-term (1–2 weeks) treatment with itraconazole or ketoconazole or other strong CYP3A4 inhibitors, but should be considered during long-term therapy. A reduction in the dose of budesonide 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 after each use with hot water and a mild detergent, thoroughly rinsed with water, and dried by connecting the nebulizer chamber to the compressor. It is recommended to inhale the aerosolized corticosteroid via mouthpiece rather than mask to prevent local skin irritation of the face. If a mask is used, the face should be washed with water after inhalation.

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

Pneumonia in patients with chronic obstructive pulmonary disease (COPD). Epidemiological studies in patients with COPD receiving inhaled corticosteroids have shown an increased incidence of pneumonia, including pneumonia requiring hospitalization. There is some evidence of increased pneumonia risk with higher corticosteroid doses, although this has not been definitively proven in any study.

There are no conclusive clinical data on within-class differences among inhaled corticosteroids regarding pneumonia risk.

Physicians should closely monitor COPD patients for possible development of pneumonia, as clinical symptoms of these conditions overlap with those of COPD exacerbation. Risk factors for pneumonia in COPD patients include current smoking, advanced age, low body mass index, and severe COPD.

Visual disturbances. Visual disturbances may occur with both systemic and local use of corticosteroids. If a patient experiences symptoms such as blurred vision or other visual disturbances, an ophthalmologist should be consulted to evaluate possible causes, which may include cataract, glaucoma, or rare conditions such as central serous chorioretinopathy, which has been reported after systemic and local corticosteroid use.

Children

Effect on growth. Regular monitoring of growth is recommended for 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 dose 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 is important.

Use during pregnancy or breastfeeding

Pregnancy.

Most data from prospective epidemiological studies and post-marketing international experience have not shown an increased risk of adverse effects on the fetus/newborn with inhaled budesonide use during pregnancy.

Animal studies have demonstrated that glucocorticosteroids can cause developmental abnormalities. However, these findings are not considered significant for humans when recommended doses are used, but inhaled budesonide therapy should be regularly reviewed and the drug used at the lowest effective dose.

Proper management of bronchial asthma is important for both the fetus and the mother 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 less pronounced systemic effects when doses necessary for equivalent respiratory response are used.

Breastfeeding.

Budesonide is excreted in breast milk. However, no effects on the breastfed infant are expected when the drug is used at therapeutic doses.

The medicinal product Budesonide-Teva may be used during breastfeeding.

Maintenance treatment with inhaled budesonide (200 mcg or 400 mcg twice daily) in breastfeeding women with bronchial asthma results in only minimal systemic exposure of budesonide in breastfed infants. Pharmacokinetic study data indicate that the calculated daily infant dose is 0.3% of the maternal daily dose for both dose levels, and the average drug concentration in infant plasma is estimated to be 1/600 of the concentration observed in maternal plasma, assuming complete oral bioavailability in the infant. Budesonide concentrations in all infant plasma samples were below the lower 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 the drug is used at therapeutic doses.

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

The medicinal product Budesonide-Teva has no effect or negligible effect on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Dosage

Dosage must be adjusted according to individual patient needs.

The dose administered to a 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 required 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

Initial Therapy

At the beginning of treatment, during exacerbations of bronchial asthma, and when reducing or discontinuing oral glucocorticoids, the recommended dosage is:
Children aged 6 months to 12 years: 0.5–1.0 mg twice daily.

Adults (including elderly patients) and children aged 12 years and older: 1.0–2.0 mg twice daily. In very severe cases, the dose may be further increased.

Maintenance Therapy

The maintenance dose should be individually tailored to each patient’s needs, taking into account disease severity and clinical response. Once therapeutic effect is achieved, the maintenance dose should be reduced to the lowest level sufficient for symptom control.

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

Adults (including elderly patients) and children aged 12 years and older: 0.5–1.0 mg twice daily.

Patients receiving oral glucocorticoids as maintenance therapy

Treatment with the medicinal product Budesonide-Teva allows for discontinuation or significant reduction of oral glucocorticoid dosage while maintaining control of bronchial asthma. A prerequisite for initiating the switch from oral steroids is a relatively stable clinical condition. For approximately 10 days, a high dose of budesonide should be administered 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 inhaled budesonide alone. For further details on discontinuation of oral glucocorticoids, see the section «Special Warnings and Precautions for Use».

Dosage Considerations

The medicinal product Budesonide-Teva may be mixed with 0.9% sodium chloride solution and with nebulization solutions containing terbutaline, salbutamol, fenoterol, acetylcysteine, sodium cromoglicate, or ipratropium bromide.

Table 1

Dosage Recommendations

Dose (mg)	Volume of medicinal product Budesonide-Teva, 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

* Use 2 ampoules of the medicinal product Budesonide-Teva, suspension for nebulization, 0.25 mg/mL or one ampoule of the medicinal product Budesonide-Teva, suspension for nebulization, 0.5 mg/mL.

** Use one ampoule of the medicinal product Budesonide-Teva, suspension for nebulization, 0.25 mg/mL plus one ampoule of the medicinal product Budesonide-Teva, suspension for nebulization, 0.5 mg/mL.

For patients in whom an enhanced therapeutic effect is desired, particularly those without excessive mucus in the airways, increasing the dose of inhaled budesonide is recommended instead of combined treatment with oral corticosteroids, due to a lower risk of systemic adverse effects.

Croup

The usual dose for children with croup is 2 mg of nebulized budesonide. This dose may be administered as a single dose or divided into two 1 mg doses given 30 minutes apart. Administration of the medicinal product may be repeated every 12 hours, up to a maximum of 36 hours or until clinical improvement is achieved.

Method of administration

Note! Ultrasonic nebulizers are not suitable for nebulization of Budesonide-Teva and therefore cannot be recommended for use.

Treatment with Budesonide-Teva is performed using a jet nebulizer with a mouthpiece or an appropriate 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.

Instructions for use:

• Prepare the nebulizer for use according to the manufacturer's instructions.
• Open the outer foil package and remove the blister pack containing ampoules. Detach one ampoule from the pack by twisting and pulling apart (Fig. 1).
• Gently shake the ampoule for approximately 10 seconds or until the sediment disappears.
• Holding the ampoule in an upright position, unscrew the top cap (Fig. 2).
• Invert the ampoule and squeeze its contents into the nebulizer chamber (Fig. 3).
• The ampoule is intended for single use only. After each use, any unused medicinal product should be discarded, and the nebulizer chamber should be rinsed and cleaned. The nebulizer chamber and mouthpiece or face mask should be washed with warm water or mild detergent, thoroughly rinsed, and dried by attaching the nebulizer chamber to the compressor inlet.
• Patients should be advised to rinse their mouth with water after inhalation of the prescribed dose to minimize the risk of developing oropharyngeal candidiasis.
• Additionally, patients should also rinse their face with water after using a face mask to prevent skin irritation.

Children.

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

Overdose.

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

Adverse Reactions

Adverse reactions are classified by frequency according to the following criteria: 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); and frequency not known (cannot be estimated from available data).

Infections and infestations. Common: oropharyngeal candidiasis, pneumonia (in patients with COPD).

Immune system disorders. Rare: immediate- and delayed-type hypersensitivity reactions*, including rash, contact dermatitis, urticaria, angioedema, and anaphylactic reaction.

Endocrine disorders. Rare: signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation**.

Psychiatric disorders. Uncommon: anxiety, depression. Rare: restlessness, nervousness, behavioural changes (mainly in children), sleep disturbances, psychomotor hyperactivity, aggression.

Nervous system disorders. Uncommon: tremor***.

Eye disorders. Uncommon: cataract, blurred vision. Frequency not known: glaucoma.

Respiratory, thoracic and mediastinal disorders. Common: cough, throat irritation, hoarseness. Rare: bronchospasm, dysphonia, hoarseness****.

Gastrointestinal disorders. Common: irritation of the oral mucosa, dysphagia.

Skin and subcutaneous tissue disorders. Rare: bruising, skin reactions, pruritus, erythema.

Musculoskeletal and connective tissue disorders. Uncommon: muscle spasms.

Investigations. Very rare: decreased bone mineral density.

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

** see section "Paediatric population" below;

*** based on frequency recorded during clinical trials;

**** rare in children.

Occasionally, when a nebulizer with a face mask has been used, hypersensitivity reactions in the form of facial skin irritation have been reported. To prevent irritation, wash the face after each use of the face mask.

With systemic exposure to inhaled glucocorticosteroids, symptoms or signs of adverse reactions typical of systemic glucocorticosteroids may occasionally occur. These are likely to depend on dose, duration of exposure, concomitant and prior corticosteroid treatment, and individual sensitivity (see section "Special warnings and precautions for use").

Description of selected adverse reactions

Occasionally, when a nebulizer with a face mask was used, hypersensitivity reactions in the form of facial skin irritation have been reported. To prevent irritation, wash the face after each use of the face mask.

Oropharyngeal candidiasis may occur during treatment with inhaled budesonide. Experience shows that the incidence of candidiasis can be reduced by rinsing the mouth after each inhalation to minimize this risk.

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

In placebo-controlled clinical trials, cases of cataract were reported uncommonly also in the placebo group.

Results from clinical trials involving 13,119 patients treated with inhaled budesonide and 7,278 patients treated with placebo were analysed. 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.

Paediatric population

Due to the risk of growth retardation in children, growth monitoring should be performed in paediatric patients as described in section "Special warnings and precautions for use".

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions during the post-marketing period. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Shelf life after opening the foil pouch – 3 months. The contents of the ampoule should be used immediately after opening.

Storage conditions. Store the medicinal product at a temperature not exceeding 25 °C. Do not freeze. Store in an upright position. Ampoules in an opened foil pouch should be stored in the cardboard box to protect from light. Keep out of reach and sight of children.

Packaging. 2 ml in an ampoule; 5 ampoules in a foil pouch; 4 pouches in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Norton Healthcare Limited T/A IVAX Pharmaceuticals UK.

Manufacturer's address and place of business.

Aston Lane North, Whitehouse Vale Industrial Estate, Runcorn, WA7 3FA, United Kingdom.