BUDESONIDE ZENTIVA 1 mg/2 ml Susp p inh/nébulis en récipient unidose 4Sach/5unid

Micronized budesonide.................................................................................................................................... 1 mg

For a single-dose container of 2 ml.

BUDESONIDE ZENTIVA, suspension for inhalation by nebuliser in single-dose container, is indicated:

• as maintenance treatment of asthma in adults, adolescents and children when pressurised or dry powder inhalers cannot be used or are unsuitable.

Dosage

The initial dose will be determined according to the severity of the asthma before treatment and will then be adjusted according to individual results.

Adults: 0,5 mg to 4 mg per day.

Child: 0,25 mg to 2 mg per day. The dose of 2 mg is reserved for the treatment of severe asthma.

Administrations are usually divided into 2 nebulisation sessions per day. A daily dose of up to 1 mg may be administered in a single nebulisation session per day.

The suspension contained in the single-dose container is sterile. The unused quantity remaining in the opened single-dose container must be discarded.

After several days (or weeks) of initial treatment, when the clinical condition has improved, symptoms have regressed and asthma is controlled, the minimum effective dose should be sought. To this end, the daily dose may be administered as one nebulisation session per day, if this dosing schedule promotes treatment compliance.

In case of destabilisation of the asthma, the dose and number of doses should be increased again.

In children under 5 years presenting with recurrent episodes of bronchial wheezing, a course of inhaled budesonide of 2 to 3 months may be considered in order to determine whether it is asthma. A significant improvement in symptoms under corticosteroid treatment and their reappearance on discontinuation of treatment should suggest the diagnosis of asthma. Treatment with BUDESONIDE ZENTIVA, nebulisation should be stopped if no clinical benefit is observed within 2-3 months. Unless the diagnosis of asthma is confirmed, budesonide treatment should not be continued for more than 3 months to avoid unjustified prolonged exposure (see section Warnings and precautions.and 4.8).

Method of administration

This budesonide suspension should be administered by inhalation using a compressed air (or pneumatic) nebuliser device. Ultrasonic generators are not recommended as they may not be suitable for correct administration of BUDESONIDE ZENTIVA.

NOT FOR INJECTION – NOT TO BE SWALLOWED

The BUDESONIDE ZENTIVA suspension is ready to use.

Patients should be informed that they must carefully follow the manufacturer's instructions for the use and maintenance of the nebulisation device.

A filling volume of 2 to 4 ml is suitable for most nebulisers. If necessary, top up to the recommended volume with sterile saline.

The resulting mixture is pulsed by air or oxygen flow (6 to 8 litres per minute) for about 10 to 15 minutes during which the patient breathes at their usual rate.

The technique of use by the patient must be checked regularly.

After inhalation, the unused suspension remaining in the nebulizer chamber must be discarded.

The patient should be advised to rinse their mouth after each nebulisation session in order to reduce the risk of oropharyngeal candidiasis, and to rinse their face with water when using a face mask in order to reduce the risk of local skin irritation on the face.

Hypersensitivity to the active substance or to any of the excipients listed in section Composition.

Inform the patient that this medicine is not intended to abort an established asthma attack, but is a continuous maintenance treatment of asthma to be continued regularly, daily and at the prescribed doses, and whose effects on asthma symptoms will only be felt after a few days to a few weeks.

If, despite well-conducted treatment, paroxysmal dyspnoea occurs, a fast-acting, short-acting inhaled beta2 mimetic bronchodilator should be used to treat the acute symptoms. The patient should be informed of this and told that an immediate medical consultation is necessary if, in this case, the usual relief is not rapidly observed after inhalation of the beta2 mimetic bronchodilator.

If a patient develops, over a few days, a rapid increase in their use of fast-acting, short-acting inhaled beta2 mimetic bronchodilators, a decompensation of their disease and the possibility of progression to severe acute asthma (status asthmaticus) must be feared (especially if peak flow values fall and/or become irregular). The physician should also inform the patient that, in this case, an immediate consultation is necessary. The therapeutic management should then be reassessed.

The patient must be warned that improvement in their clinical condition must not lead to a change in their treatment, in particular stopping inhaled corticosteroid therapy, without medical advice.

In case of bronchial infection or abundant bronchorrhea, appropriate treatment is necessary in order to promote optimal distribution of the product in the airways.

In case of destabilisation of asthma, or insufficient control of asthma exacerbations despite maximum doses of inhaled corticosteroids, a short course of systemic corticosteroid therapy should be considered. It is then necessary to maintain inhaled corticosteroid therapy in association with the systemic treatment.

Inhaled corticosteroid therapy may cause systemic effects, particularly during high-dose or prolonged treatment. The occurrence of these effects with the inhaled route is much less likely than during oral corticosteroid therapy. Possible systemic effects are: Cushing's syndrome or cushingoid appearance, skin thinning, subcutaneous bruising, adrenal insufficiency, growth retardation in children and adolescents, decreased bone mineral density, cataract and glaucoma and, more rarely, psychological and behavioural disorders including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggressiveness (particularly in children). It is important to always seek the minimum effective dose of inhaled corticosteroids that achieves control of asthma symptoms.

Potential effects on bone mineral density should be kept in mind, particularly in patients receiving high doses of inhaled corticosteroids over the long term and presenting risk factors for osteoporosis. No significant effects on bone mineral density have been demonstrated in long-term clinical studies conducted in children receiving on average 400 µg/day (nominal dose) of budesonide or in adults receiving 800 µg/day (nominal dose) of budesonide. No data are available regarding the effect at higher doses.

Patients who have required high doses of corticosteroids in emergency situations or who have received long-term inhaled corticosteroid therapy at the maximum recommended doses may develop adrenal insufficiency. These patients may show signs and symptoms of adrenal insufficiency during situations of severe stress. Signs of acute adrenal insufficiency may be non-specific: anorexia, abdominal pain, weight loss, fatigue, headache, nausea, vomiting, loss of consciousness, convulsions, hypotension and hypoglycaemia. Supplementary corticosteroid therapy should be considered in situations likely to trigger stress or in the case of scheduled surgery.

Concomitant administration of inhaled corticosteroids in patients on long-term oral corticosteroid therapy (corticosteroid-dependent patients) does not remove the need for necessary precautions when reducing oral corticosteroid doses. These should be reduced very gradually, and withdrawal should be carried out under careful medical supervision (watching for the appearance of signs of acute or subacute adrenal insufficiency), which may persist for a prolonged period after cessation of systemic corticosteroid therapy.

When replacing oral corticosteroid therapy with inhaled corticosteroid therapy, the systemic effect of the corticosteroid is reduced, which may lead to the reappearance of allergic symptoms (such as rhinitis, eczema) and/or rheumatological symptoms (such as muscle and joint pain). Specific treatment should be instituted. Corticosteroid-adrenal insufficiency should be suspected if, in rare cases, the following symptoms occur: fatigue, headache, nausea and vomiting. A temporary increase in oral corticosteroid doses may then sometimes be necessary.

In cases of active or quiescent pulmonary tuberculosis or pulmonary fungal infection, close monitoring and appropriate treatment are essential.

Inhaled corticosteroid therapy may cause oropharyngeal candidiasis, which may require antifungal treatment and discontinuation of inhaled corticosteroid therapy (see also section Dosage and administration).

As with other inhaled products, bronchospasm may occur, manifesting as an increase in wheezing, dyspnoea and cough immediately after taking the medicine. Bronchospasm will be treated with a fast-acting bronchodilator, which must be administered immediately. Treatment with BUDESONIDE ZENTIVA must be stopped immediately and the therapeutic management will be reassessed to consider, if necessary, therapeutic alternatives.

Visual disturbances may occur with systemic or local corticosteroid therapy. In case of blurred vision or the appearance of any other visual symptom during corticosteroid therapy, an ophthalmological examination is required to look for cataract, glaucoma, or rarer lesions such as central serous chorioretinopathy, as described with systemic or local administration of corticosteroids.

In case of hepatic impairment, the elimination of corticosteroids is reduced and consequently exposes patients to higher systemic concentrations and an increased risk of systemic effects. Caution is required in cases of hepatic impairment.

Athletes' attention is drawn to the fact that this medicine contains an active substance that may induce a positive result in tests carried out during anti-doping controls.

Paediatric population

An initial slight but generally transient slowing of growth (about 1 cm) has been observed, which usually appears during the 1st year of treatment. Long-term studies in clinical practice suggest that children and adolescents treated with inhaled budesonide reach their predicted adult height on average. However, in a long-term, double-blind clinical study in which the administered dose of inhaled budesonide was generally not adjusted to the minimum effective dose, children and adolescents treated with inhaled budesonide reached an adult height on average 1,2 cm shorter than those randomised to placebo. The growth of children receiving long-term inhaled corticosteroid therapy must be monitored regularly. If growth slows, treatment should be re-evaluated with a view to reducing the doses of the inhaled corticosteroid.

The expected benefits of corticosteroid therapy must be carefully weighed against the possible risks of growth retardation. The opinion of a paediatric pulmonology specialist may be required.

The decision to start inhaled budesonide treatment in children up to 5 years of age with recurrent episodes of bronchial wheezing must take into account the severity and frequency of wheezing episodes. Regular follow-up is essential in order to reassess the response to treatment. If no clinical benefit is observed under treatment within 2-3 months, or if the diagnosis of asthma is not confirmed, budesonide treatment must be stopped in order to avoid unjustified prolonged exposure to inhaled corticosteroids and the associated risks of growth retardation (see section Dosage and administration and section Adverse effects.).

Associations to be taken into account

+ ritonavir, ketoconazole, itraconazole

Increased plasma concentrations of budesonide due to decreased hepatic metabolism by the enzyme inhibitor, with risk of onset of Cushing's syndrome.

Budesonide is mainly metabolised by cytochrome CYP P450 3A4. A significant increase in blood budesonide levels may be observed with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and HIV protease inhibitors). Concomitant use of these medicines should be avoided. If this combination cannot be avoided, a sufficiently long interval must be respected between administration of the CYP3A4 inhibitor and budesonide (see section Pharmacokinetics.).

Pregnancy

Available data from a large number of pregnancies have not revealed an increased teratogenic risk associated with the use of inhaled budesonide. In animals, glucocorticoids induce malformations (see section Preclinical safety). However, these observations do not appear relevant to pregnant women at therapeutic doses.

It is important for both the foetus and the mother to maintain adequate asthma treatment during pregnancy.

Budesonide may be administered during pregnancy if the expected benefit to the mother outweighs the risks to the foetus.

Breast-feeding

Budesonide is excreted in breast milk. However, a pharmacokinetic study showed that after administration of inhaled budesonide at doses of 200 or 400 µg twice daily, systemic exposure to budesonide in breastfed children was negligible. At therapeutic doses, no effect on the breastfed child is expected.

Budesonide may be used during breastfeeding if necessary.

Inhaled budesonide has no effect on the ability to drive vehicles and use machines.

Adverse events attributable to budesonide are presented below by organ class and by frequency. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10 000 and < 1/1000) and very rare (< 1/10 000) and not known (the frequency of occurrence cannot be estimated from the available data).

Description of the adverse effect: skin irritation at the level of the face

Cases of facial irritation have been reported with use of a facial mask for nebulisation. It is recommended to rinse the face with water after a nebulisation session using a facial mask.

Systemic effects

Occasionally, signs and symptoms of systemic side effects related to glucocorticoids may occur when using inhaled glucocorticoids (see section Warnings and precautions).

* Paediatric population

Given the risk of growth slowdown in the paediatric population, the growth of children and adolescents should be monitored regularly (see section Warnings and precautions.).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/

Use of this medicine at doses far above the recommended doses reflects a worsening of the respiratory condition requiring prompt consultation for therapeutic reassessment.

An acute overdose of inhaled budesonide should not have any clinical impact.

Pharmacotherapeutic class: ANTI-ASTHMATIC INHALED GLUCOCORTICOID, ATC code: R03BA02 (R: Respiratory system)

Budesonide, by inhalation, exerts a marked anti-inflammatory action on the bronchial mucosa.

In adults, the suppressive effect of budesonide on the hypothalamic-pituitary-adrenal axis only occurs at a dose greater than or equal to 1600 µg/24 hours.

Absorption

In adults, the systemic bioavailability of budesonide after administration of budesonide inhalation suspension by nebuliser using a compressed-air nebuliser is approximately 15% of the nominal dose and 40 to 70% of the dose actually delivered to patients. A small fraction of the circulating amount of budesonide originates from the swallowed medicinal product. The maximum concentration reached approximately 10 to 30 minutes after the start of nebulisation is approximately 4 nmol/L for an administered dose of 2 mg.

Distribution

Budesonide has a volume of distribution of 3 litres/kg. Binding to plasma proteins is approximately 85 to 90%.

Biotransformation

Budesonide undergoes an extensive hepatic first-pass effect (90%) with transformation into metabolites that have practically no glucocorticoid activity. The glucocorticoid activity of the main metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1%.

Budesonide is mainly metabolized by cytochrome CYP450 3A.

Elimination

Budesonide metabolites are excreted in the urine, partly in conjugated form. Budesonide is found in negligible amounts in unchanged form.

The plasma clearance of budesonide is high (approximately 1,2 L/min) and the plasma half-life after intravenous administration is 2 to 3 hours.

LLinearity/non-linearity

The kinetics of budesonide are linear at the recommended therapeutic doses.

Paediatric population

The plasma clearance of budesonide is approximately 0,5 L/min in asthmatic children aged 4 to 6 years. It is approximately 50% higher than in adults. The terminal half-life of budesonide after inhalation is approximately 2,3 hours in asthmatic children. It is approximately the same in healthy adults.

After administration of budesonide inhalation suspension by nebuliser using a compressed-air nebuliser (Pari LC Jet Plus fitted with a Pari Master compressor), the systemic bioavailability in asthmatic children aged 4 to 6 years is approximately 6% of the nominal dose and 26% of the delivered dose, i.e. a systemic bioavailability approximately 50% of that observed in healthy adults. The systemic exposure to budesonide (Cmax and AUC) after nebulised administration of a single dose of 1 mg to children aged 4 to 6 years is comparable to that observed in healthy adults.

Pharmacokinetic interaction with CYP450 3A4 inhibitors:

Plasma concentrations of budesonide were 6 times higher when oral budesonide (single dose of 3 mg) was co-administered with ketoconazole 200 mg once daily. When ketoconazole was administered 12 hours after budesonide, plasma budesonide concentrations were only increased by a factor of 3, reflecting a smaller pharmacokinetic interaction when the products are administered at a distance. Limited data with high-dose budesonide also indicate a significant increase in plasma budesonide levels (on average by a factor of 4) when itraconazole 200 mg once daily is co-administered with inhaled budesonide (single dose of 1000 µg).

In animals, the toxicity of budesonide is related to an exacerbation of the glucocorticoid pharmacological effect.

Malformations were observed in animal reproduction studies with glucocorticoids such as budesonide (cleft palate, skeletal malformation). However, these experimental findings in animals are not extrapolable to humans at the recommended doses.

3 years.

3 months after opening the protective sachet.

Once the protective sachet is opened, the unit doses must be kept protected from light in the sachet and used within 3 months.

As the suspension contained in the unit dose is sterile, any unused suspension remaining in the unit dose must be discarded after use.

No special requirements.

• Indication(s) appearing in the marketing authorisation at the date of publication of this decree
• Asthma in adults and children, maintenance treatment of 2e intention (of)