BECLOMETASONE CHIESI 800 µg/2 ml Susp inh par nébuliseur 4Sach/5unid

Suspension (whitish) for inhalation by nebuliser.
Single-dose container containing 2 ml of suspension*. Box of 20, under 4 heat-sealed sachets of 5.

^* The container of BECLOMETASONE CHIESI 800 micrograms has a mark indicating half of the contents (corresponding to 400 micrograms).

For 2 ml of suspension:

Beclometasone dipropionate anhydrous: 800 micrograms

Excipients:

BECLOMETASONE CHIESI is indicated:

• for continuous treatment of asthma in adults and children, when pressurised or dry powder inhalers cannot be used or are unsuitable;
• for treatment of children aged 5 years or under with recurrent episodes of wheezing (see sections Dosage and administration and Warnings and precautions : Paediatric population).

Dosage

The initial dose of beclometasone dipropionate by nebulisation will be determined according to the frequency and severity of symptoms.

The recommended initial doses are:

• adults and adolescents (from 12 years of age): 800 to 1 600 micrograms twice a day, i.e. 1 to 2 single-dose containers to be nebulised 2 times a day (corresponding to a total daily dose of: 1 600 to 3 200 micrograms)
• children (up to 11 years of age): 400 to 800 micrograms twice a day, i.e. 1/2 to 1 single-dose containers to be nebulised 2 times a day (corresponding to a total daily dose of: 800 to 1 600 micrograms)

In the majority of cases, daily doses of 3 200 micrograms in adults and adolescents, and of 1 600 micrograms in children up to the age of 11 years, should not be exceeded.

Once asthma control improves or wheezing disappears, the daily dose should be reduced to the minimum effective dose and administration as a 1 single daily dose should be considered.

BECLOMETASONE CHIESI must be administered daily and regularly; the duration of treatment will depend on symptoms.

In children with recurrent episodes of bronchial wheezing, treatment with BECLOMETASONE CHIESI should be stopped if no clinical benefit is observed within 2-3 months. Unless the diagnosis of asthma is confirmed, treatment with BECLOMETASONE CHIESI should not be continued for more than 3 months to avoid unjustified prolonged exposure (see section Warnings and precautions).

Method of administration

For inhalation use only.

BECLOMETASONE CHIESI must not be injected or administered orally.

BECLOMETASONE CHIESI must be administered using a mouthpiece or a suitable face mask connected to a compressed air (or pneumatic) nebuliser combined with a compressor.

Patients should be informed that they must carefully follow the manufacturer's instructions for use of the nebulisation device. Incorrect use of the nebulisation device may lead to inadequate administration of the treatment.

The use of ultrasonic nebulisers is not recommended as they are not suitable for administration of BECLOMETASONE CHIESI.

Instructions concerning preparation and dilution of the medicinal product: see section Disposal and handling.

Patients should be advised to rinse their mouth with water after each nebulisation session in order to reduce the risk of oropharyngeal candidiasis (see section Warnings and precautions).

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

Asthma treatment is carried out in successive steps depending on the clinical response and the results of respiratory function tests.

BECLOMETASONE CHIESI is not intended to relieve acute asthma symptoms. In these situations, a short-acting inhaled beta-2 agonist should be used, which each patient must have available at all times as rescue treatment.

An increase in the use of bronchodilators to relieve symptoms, in particular short-acting inhaled beta-2 agonists, is a sign of deterioration in asthma control. If the patient experiences a reduced effect from their rescue treatment or needs a greater number of inhalations than usual, medical advice is required. The therapeutic approach must be reassessed and an increase in anti-inflammatory treatment (increase in the dose of inhaled corticosteroids or short courses of oral corticosteroids) should be considered.

Severe asthma exacerbations are managed with standard treatment (i.e., increasing the dose of inhaled beclometasone dipropionate and, if necessary, systemic corticosteroid therapy and/or antibiotic therapy, and use of beta-2 agonists).

Systemic effects may occur during treatment with inhaled corticosteroids, particularly when high doses are administered over the long term. However, the risk of systemic repercussions remains lower with inhaled corticosteroids than with oral corticosteroids. Possible systemic effects are: suppression of the hypothalamic-pituitary-adrenal axis, 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). Therefore, the clinical condition of patients should be monitored regularly and the minimum effective dose of inhaled corticosteroids sought at all times to maintain asthma control.

On cessation of systemic corticosteroid therapy, some patients may experience a sensation of general malaise for approximately 2 weeks even though their respiratory function is stable or even improving. These patients should be encouraged to continue treatment with inhaled beclometasone dipropionate without resuming systemic corticosteroid therapy, unless objective clinical signs of adrenal insufficiency appear.

Initiating treatment with BECLOMETASONE CHIESI as a replacement for prolonged or high-dose systemic corticosteroid therapy must be carried out with caution, as inhibition of adrenocortical function may persist for some time. In all cases, beclometasone dipropionate will be administered without interrupting systemic corticosteroid therapy. After approximately one week, the latter will be gradually reduced at a rate determined by the maintenance dose of systemic corticosteroid therapy and under regular monitoring, with possible adrenocortical function tests to adjust the dose of inhaled beclometasone dipropionate.

Caution is required in patients with active or latent pulmonary tuberculosis or other types of infection. Patients with tuberculosis must receive antituberculous treatment when starting treatment with beclometasone dipropionate.

Caution is required in patients with viral, bacterial or fungal infections of the eyes, mouth, or respiratory tract. In the case of a bacterial respiratory tract infection, concomitant appropriate antibiotic therapy may be necessary.

The occurrence of oropharyngeal candidiasis appears to be more frequent with higher corticosteroid doses and prolonged treatment. This infection generally responds to appropriate antifungal treatment applied locally, without interrupting beclometasone dipropionate.

Patients should be advised to rinse their mouth with water immediately after inhalation to reduce the risk of oral candidiasis.

Hoarseness that may occur with treatment is reversible and disappears on discontinuation of treatment and/or with voice rest.

Paradoxical bronchospasm may occur, manifesting as an increase in wheezing, dyspnoea and cough immediately after taking the medicine. Bronchospasm must be treated immediately with a fast-acting inhaled bronchodilator. Treatment with BECLOMETASONE CHIESI must be stopped immediately and the therapeutic approach reassessed to consider, where appropriate, an alternative treatment.

Reduction or withdrawal of oral corticosteroid therapy may reveal clinical signs suggestive of Churg-Strauss syndrome or hypereosinophilia.

Replacing systemic corticosteroid therapy with an inhaled treatment may sometimes reveal the existence of allergies manifesting as allergic rhinitis or eczema previously controlled by systemic corticosteroid therapy. Symptomatic treatment including antihistamines and/or topical corticosteroid treatment is recommended.

Athletes should be made aware that this product contains an active substance that may induce a positive reaction in tests carried out during anti-doping controls.

Visual disturbances:

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.

Paediatric population

The decision to initiate inhaled beclometasone dipropionate treatment in children under 5 years of age presenting 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, treatment with BECLOMETASONE CHIESI must be stopped in order to avoid unjustified prolonged exposure to inhaled corticosteroids and the associated risks of growth retardation (see section Adverse effects).

The growth of children receiving prolonged treatment with inhaled corticosteroids must be regularly monitored. In case of growth slowdown, the treatment should be reassessed in order to reduce the dose of the inhaled corticosteroid. The expected benefits of corticosteroid therapy must be carefully weighed against the potential risks of growth slowdown. The opinion of a pediatric pulmonology specialist may be required.

The data available on the effect of inhaled corticosteroid therapy on the growth of infants and young children under 2 years are limited.

Pharmacokinetic interactions

No specific pharmacokinetic drug interaction study has been conducted.

Beclometasone dipropionate undergoes very rapid pre-systemic metabolism by esterase enzymes, without involvement of cytochrome P450.

The metabolism of beclometasone is less dependent on CYP3A than that of certain other corticosteroids, and interactions are unlikely in the majority of cases. Nevertheless, in case of concomitant use of potent CYP3A inhibitors (e.g. ritonavir, cobicistat), the risk of systemic effects cannot be ruled out. Caution and appropriate monitoring are required in case of concomitant treatment.

Pharmacodynamic interactions

Concomitant administration of corticosteroids by the systemic or intranasal route exerts an additive inhibitory effect on adrenal function.

Pregnancy

According to published data, no teratogenic effect has been demonstrated in pregnant women using inhaled beclometasone. However, a possible effect on fetal development after inhalation of high doses of beclometasone dipropionate cannot be excluded.

Studies performed in animals have demonstrated reproductive toxicity (see section Preclinical safety).

Potential risks to the fetus or newborn must be taken into consideration against the potential benefit of inhaled beclometasone dipropionate for the mother. If treatment proves necessary during pregnancy, the lowest effective dose of beclometasone dipropionate should be used.

Newborns and infants born to mothers who received significant doses of beclometasone dipropionate during pregnancy should be monitored to detect any possible inhibition of adrenal function.

Breast-feeding

As with other corticosteroids, it is probable that beclometasone dipropionate and its metabolites are excreted in breast milk. Nevertheless, at the therapeutic dose of beclometasone dipropionate, no effect is expected in breastfed newborns/infants.

No harmful effect of glucocorticoids has been demonstrated in breastfed infants. The benefits of breastfeeding should outweigh a theoretical risk.

Beclometasone dipropionate may be used during breastfeeding. However, in case of inhalation of a high dose of beclometasone dipropionate, it is preferable to avoid breastfeeding within 4 hours following administration.

Fertility

No specific study has been conducted regarding the effect of beclometasone dipropionate on human fertility. Studies performed in animals have demonstrated some decrease in fertility, but only at high doses.

BECLOMETASONE CHIESI has no or negligible influence on the ability to drive vehicles and use machines.

Summary of the safety profile

The most frequently observed adverse reactions in clinical trials with beclometasone dipropionate in the treatment of asthma and in children with wheezing were laryngitis, pharyngitis and oropharyngeal candidiasis.

Rare cases of severe hypersensitivity reactions including angioedema of the eyelids, face, lips and throat (Quincke's edema) have been reported.

Paradoxical bronchospasm may occur following administration of the product.

Tabulated summary of adverse reactions

The adverse reactions observed in clinical trials conducted with inhaled beclometasone in the treatment of asthma and wheezing in children are listed in the table below by MedDRA system organ class and frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1 000, < 1/100); rare (≥ 1/10 000, < 1/1 000); very rare (< 1/10 000); frequency not known (cannot be estimated from the available data).

System organ class	Adverse reaction	Frequency
Infections and infestations	Laryngitis, pharyngitis	Very common
	Oropharyngeal candidiasis	Common
	Herpes simplex	*Rare
Endocrine disorders	Inhibition of adrenal function**	Very rare
Immune system disorders	Hypersensitivity reactions: angioedema, skin rash, urticaria, pruritus	*Rare
Psychiatric disorders	Psychomotor hyperactivity, sleep disorders, anxiety, depression, aggression, behavioural disorders (mainly in children)	Frequency not known
Nervous system disorders	Headache	Uncommon
	Tremor	*Rare
Respiratory, thoracic and mediastinal disorders	Cough	Common
	Throat irritation, hoarseness, dysphonia, paradoxical bronchospasm, wheezing	Uncommon
	Dyspnoea	Rare
Eye disorders	Cataract**, glaucoma**	Very rare
	Blurred vision (see section Warnings and precautions)	Frequency not known
Gastrointestinal disorders	Nausea, dyspepsia	Common
Musculoskeletal and connective tissue disorders	Growth retardation* (in children and adolescents), decrease in bone mineral density*	Very rare
General disorders and administration site conditions	Asthenia	*Rare

* adverse effects derived from spontaneous reports

** systemic effects of inhaled corticosteroids

Description of selected adverse reactions

The systemic effects of inhaled corticosteroids (such as beclomethasone dipropionate) may occur particularly with long-term administration of high doses. Inhibition of adrenal function, decreased bone mineral density, growth retardation in children and adolescents, cataract and glaucoma have been reported (see section Warnings and precautions).

Precautions to reduce the risk of oral candidiasis, hoarseness and paradoxical bronchospasm are described in section Warnings and precautions.

Paediatric population

Growth retardation and behavioural disorders are observed more frequently in children than in adults, particularly with long-term administration of high doses.

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 reactions via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr.

Use of this medicinal product at doses above the recommended doses over a long period may lead to suppression of the hypothalamic-pituitary-adrenal axis. In this case, it is recommended to monitor adrenal function. Inhibition of adrenal function requires corticosteroid replacement therapy.

Treatment with BECLOMETASONE CHIESI may be continued at the minimum effective dose allowing control of symptoms (asthma or wheezing) (see section Warnings and precautions).

Administration of a high dose of corticosteroids over a very short period may lead to suppression of the hypothalamic-pituitary-adrenal axis. In this case, there is no need to initiate specific emergency treatment. Function of the hypothalamic-pituitary-adrenal axis is restored in most cases within 1 to 2 days.

Pharmacotherapeutic class: Other drugs for obstructive airway diseases, for inhalation; Glucocorticoids, ATC code: R03 BA01.

Mechanism of action

The affinity of beclomethasone dipropionate and of its main active metabolite, beclomethasone monopropionate (17-MPB), for the human glucocorticoid receptor has been established. The potency of 17-MPB is approximately 30 times greater than that of the parent molecule. Consequently, the majority of observed effects are related to systemic exposure to 17-MPB.

Pharmacodynamic effects

Beclomethasone dipropionate is a glucocorticoid with potent anti-inflammatory activity and limited mineralocorticoid activity. After inhaled administration, a local effect is obtained in the lower airways.

The systemic pharmacodynamic effects of beclomethasone dipropionate and its active metabolite 17-MPB have been evaluated by measuring effects on the function of the hypothalamic-pituitary-adrenal axis.

Results obtained in healthy volunteers showed no effect on urinary cortisol excretion for 24 h after nebulised administration of a single dose of 1 600 μg of beclomethasone dipropionate, whereas a decrease of approximately 10 % in urinary cortisol excretion was observed after a single dose of 3 200 μg, without the difference between the two doses being significant. No significant effect on morning serum cortisol levels has been reported after nebulised administration of 1 600 and 3 200 μg divided into 2 administrations per day for 3 weeks in asthmatic patients.

Clinical efficacy and safety

The studies described below are taken from the literature as data supplementing the experience acquired with the use of inhaled beclomethasone in the treatment of asthma and bronchial wheezing.

Asthma:

A study aimed at comparing the efficacy and safety of nebulised beclomethasone dipropionate versus a nebulisation suspension of fluticasone propionate was conducted in 205 adult asthmatic patients (aged 18 to 65 years) randomised over a period of 12 weeks of treatment. The results presented show similar efficacy between the two treatments on asthma control at the end of the study in terms of respiratory function, asthma exacerbations, symptoms and use of salbutamol as on-demand symptomatic treatment (Terzano et al. 2003).

Paediatric population

Asthma:

A multicentre, double-blind, double-dummy, randomised, two-parallel-group study compared the efficacy of nebulised beclomethasone dipropionate and beclomethasone dipropionate administered using a metered-dose inhaler in 151 patients aged 6 to 16 years with moderate to severe asthma treated for 4 weeks. Improvement between the start and end of the study was similar between the two treatment groups in terms of morning peak expiratory flow (primary endpoint), symptom scores and use of salbutamol as on-demand symptomatic treatment. Both treatments were well tolerated, equivalently (Bisca et al, 2003).

The efficacy and safety of beclomethasone dipropionate in the treatment of severe persistent asthma in infants and young children aged 6 months to 6 years were evaluated in comparison with a budesonide nebulisation suspension in an open, multicentre, randomised, controlled study over 14 weeks. In this study, 40,4 % and 51,7 % of patients in the beclomethasone dipropionate and budesonide groups, respectively, did not experience a severe exacerbation (primary endpoint). Both treatments were associated with a significant decrease in nocturnal bronchial wheezing and in the number of days of corticosteroid use. Neither treatment had an effect on urinary cortisol, nor on height and weight curves. The absence of effect of nebulised beclomethasone dipropionate on bone metabolism was confirmed (Delacourt et al, 2003).

Episodes of bronchial wheezing:

Beclomethasone dipropionate by nebulisation was evaluated in 276 children aged 1 to 4 years presenting with frequent episodes of wheezing in the context of a randomised, double-blind, controlled trial of 12 weeks. A significant increase in the percentage of symptom-free days (primary criterion defined by the absence of bronchial wheezing, cough, dyspnoea and night-time awakenings of the children/parents over 24 hours) was observed in the group treated with beclomethasone dipropionate administered by regular nebulisations combined with salbutamol as symptomatic treatment on demand (69,6 % ± 20.89 [SD]; p = 0.034) compared with the group of patients receiving placebo combined with salbutamol as symptomatic treatment on demand (61.0 ± 24.83 [SD]). No difference was found compared with the group treated with beclomethasone dipropionate by nebulisation and salbutamol, both administered as symptomatic treatment on demand (64.9 ± 24.74 [SD]). These results were not influenced by the presence of factors favouring the occurrence of asthma symptoms. Furthermore, the time to onset of the first asthma exacerbation was longer in children treated with beclomethasone dipropionate by nebulisation.

In terms of safety, no variation was demonstrated in morning salivary cortisol values (Papi et al. 2009).

Beclomethasone dipropionate (BDP) is a prodrug that is predominantly hydrolysed by esterase enzymes into an active metabolite, 17-beclomethasone monopropionate (17-BMP).

Absorption

After inhalation, BDP is absorbed unchanged mainly in the lung. Gastrointestinal absorption of the swallowed fraction is negligible. The main circulating active metabolite, 17-BMP, results from pulmonary deposition and gastrointestinal absorption of the swallowed fraction.

The bioavailability of orally administered BDP is negligible, but approximately 40 % of the swallowed portion is absorbed as 17-BMP. The absolute bioavailability after inhalation is approximately 2 % and 62 % of the nominal dose for BDP and 17-BMP, respectively.

Distribution

Plasma protein binding is moderate. After intravenous administration, the plasma clearance of BDP and of its active metabolite, 17-BMP, is high (150 L/h and 120 L/h, respectively), with a small volume of distribution at steady state for BDP (20 L) and greater tissue distribution for its active metabolite (424 L).

Biotransformation

The main metabolite is the active metabolite (17-BMP). Inactive metabolites, 21-beclomethasone monopropionate (21-BMP) and beclomethasone (BOH), are also formed in small amounts but contribute little to systemic exposure.

Elimination

BDP is very rapidly eliminated from the systemic circulation after metabolism by esterase enzymes located in most tissues of the body. Renal excretion of BDP and its metabolites is negligible. Faecal excretion is the main route of elimination of BDP, essentially as polar metabolites. The terminal elimination half-lives are 0,5 h and 2,7 h for BDP and 17-BMP, respectively.

Linearity/non-linearity

The measured plasma concentrations of the active metabolite 17-BMP show almost linear kinetics.

Special populations

The pharmacokinetics of BDP have not been studied in patients with renal or hepatic impairment. However, BDP is very rapidly metabolised into the polar metabolites 21-BMP, 17-BMP and BOH by digestive, serum, pulmonary and hepatic esterases. Consequently, no change in the pharmacokinetics or safety profile of BDP is expected in cases of hepatic impairment. As no trace of BDP or its metabolites has been found in urine, no increase in systemic exposure is expected in patients with renal impairment.

In preclinical studies, the toxic effects of beclomethasone dipropionate were limited to effects associated with an exacerbation of its known pharmacodynamic effects.

In repeated-dose toxicity studies, administration of beclomethasone dipropionate by nebulisation to rats (for 180 days) and to dogs (for 90 days) had no effect on body weight, blood cells or the airway mucosa. Hepatic and renal function remained within normal limits.

Embryolethality and a teratogenic effect were found after administration of beclomethasone by subcutaneous or oral route in animals. Animal studies indicate that administration of glucocorticoids during gestation may lead to intrauterine growth retardation, the occurrence of cardiovascular and/or metabolic disorders and/or neurobehavioural disorders in adult animals.

No genotoxic effect of beclomethasone dipropionate was demonstrated.

A 95-week study in rats treated by inhalation did not demonstrate a carcinogenic effect.

This medicine must not be mixed with other medicines, except those mentioned in the section Disposal and handling.

2 years.

Use the containers within 3 months of the first opening of the sachet.

After first opening of the container containing 800 μg, it must be stored in the refrigerator (between 2 °C and 8 °C). The remaining quantity of the suspension must be used within 12 hours of first opening the container.

Store unit-dose containers upright in the original packaging (cardboard carton) to protect them from light.

The vial must be used in accordance with the following instructions:

1. Bend the container backwards and forwards (Figure A). 
2. Carefully detach a new container from the strip, starting from the top, then the middle (Figure B), leaving the other containers in the sachet. 
3. Shake the container vigorously and invert it up and down to homogenise the suspension. Repeat this until the entire contents are completely dispersed and mixed (Figure C). 
4. Open the container by turning the top part, as indicated by the arrow above (Figure D). 
5. Gently press the container to pour its contents into the nebuliser reservoir (Figure E). 

The container must be opened immediately before administration.

If only half of the dose of BECLOMETASONE CHIESI 800 micrograms is needed, turn the container over, making sure the graduation mark is clearly visible, then press the container moderately. Pour the contents carefully until the graduation mark is reached without exceeding it. Once half of the contents have been poured, replace the cap by pushing on the container. The closed container must be stored between 2 and 8 °C (in a refrigerator) and the remaining quantity of the suspension must be used within 12 hours after the container is first opened.

BECLOMETASONE CHIESI may be diluted. In this case, the contents of the container must be emptied into the nebuliser reservoir. The required quantity of 9 mg/ml (0,9 %) sodium chloride solution is to be added to it. After closing the nebuliser reservoir again, gently agitate the nebuliser to mix the contents.

ONLY a 9 mg/mL (0,9 %) sodium chloride solution must be used.

Follow the manufacturer's instructions for the use, maintenance and cleaning of the nebuliser.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

List I

Marketing authorisation (AMM)

CIP 3400930081570 (4 sachets/5 units).

Price:

12,81 euros (4 sachets/5 units).

Social security reimbursement at 65 % based on the TFR: 12, 81 euros (4 sachets/5 units) and approved for collectivities only in the indication: "Continuous treatment of asthma in children, when pressurised or dry powder inhalers cannot be used or are unsuitable".