Cixodil

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYXODIL (CYXODIL)

Composition:

Active substance: ciclesonide;

1 inhalation (dose delivered from mouthpiece) contains 80 mcg or 160 mcg or 320 mcg of ciclesonide;

Excipients: ethanol anhydrous, norflurane (HFA-134a).

Pharmaceutical form. Pressurized inhalation, solution.

Main physico-chemical characteristics: clear, colorless solution.

Pharmacotherapeutic group. Other agents for obstructive airway diseases administered by inhalation. Glucocorticoids. ATC code R03BA08.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Ciclesonide exhibits low binding affinity to glucocorticoid receptors. After inhalation, ciclesonide is converted by enzymatic activity in the lungs into its main metabolite (C21-des-methylpropionyl-ciclesonide), which has potent anti-inflammatory activity and is therefore considered the active metabolite.

Clinical efficacy and safety

In four clinical studies, ciclesonide was shown to reduce airway hyperresponsiveness to adenosine monophosphate in patients with hyperreactive airways, with the maximum effect observed at a dose of 640 µg. In another study, pretreatment with ciclesonide for 7 days significantly reduced both early and late phases of the response following inhaled allergen challenge. It has also been demonstrated that inhaled ciclesonide treatment reduces the increase in inflammatory cells (total eosinophil count) and inflammatory mediators in induced sputum.

In a controlled study, the daily area under the plasma cortisol concentration-time curve (AUC) was compared in 26 adult patients with bronchial asthma after 7 days of treatment. Compared to placebo, treatment with ciclesonide at doses of 320, 640, and 1280 µg/day did not result in a statistically significant reduction in mean daily plasma cortisol levels (AUC (0–24)/24 hours), and no dose-dependent effect was observed.

In a clinical study involving 164 adult men and women with bronchial asthma, ciclesonide was administered at doses of 320 µg/day or 640 µg/day for 12 weeks. Following stimulation with cosyntropin at doses of 1 µg and 250 µg, no significant changes in plasma cortisol levels were observed compared to placebo.

Double-blind, placebo-controlled studies of 12 weeks' duration in adults and children aged 12 years and older demonstrated that ciclesonide treatment improved lung function as measured by FEV₁ and peak expiratory flow rate, improved control of bronchial asthma symptoms, and reduced the need for inhaled beta-2 agonists.

In a 12-week study involving 680 patients with severe bronchial asthma who had previously received 500–1000 µg of fluticasone propionate daily or its equivalent, 87.3% and 93.3% of patients remained free of exacerbations during treatment with ciclesonide at doses of 160 µg or 640 µg daily, respectively. At the end of the 12-week study period, a statistically significant difference was observed between the 160 µg/day and 640 µg/day ciclesonide doses regarding the occurrence of exacerbations after the first day of the study: 43 patients/339 (=12.7%) in the 160 µg/day group and 23 patients/341 (6.7%) in the 640 µg/day group (risk ratio = 0.526; p = 0.0134). Both ciclesonide doses provided comparable FEV₁ values after 12 weeks. Treatment-related adverse reactions were observed in 3.8% and 5% of patients receiving ciclesonide at 160 µg/day or 640 µg/day, respectively.

A further 52-week study involving 367 patients with mild to moderate bronchial asthma failed to demonstrate a significant difference in the effect of higher doses of ciclesonide (320 µg/day or 640 µg/day) compared to lower doses (160 µg/day) on asthma control.

Pharmacokinetics

Ciclesonide is formulated in the propellant HFA-134a and ethanol as a solution aerosol, which demonstrates a linear relationship between different doses, inhalation force, and systemic exposure.

Absorption

Studies with radiolabeled ciclesonide administered orally and intravenously showed incomplete absorption following oral administration (24.5%). The bioavailability of ciclesonide and its active metabolite after oral administration is negligible (<0.5% for ciclesonide, <1% for the metabolite). According to γ-scintigraphy studies, lung deposition in healthy subjects is approximately 52%. Based on this, the systemic bioavailability of the active metabolite following administration via ciclesonide metered-dose inhaler is >50%. Since the oral bioavailability of the active metabolite is <1%, the swallowed portion of inhaled ciclesonide does not contribute significantly to systemic absorption.

Distribution

After intravenous administration to healthy volunteers, the initial distribution phase of ciclesonide occurred rapidly, consistent with its high lipophilicity. The volume of distribution averages 2.9 L/kg. Total plasma clearance of ciclesonide is high (mean 2.0 L/h/kg), indicating high hepatic extraction. The plasma protein binding of ciclesonide in humans averages 99%, and for the active metabolite it is 98–99%, indicating nearly complete binding of ciclesonide/active metabolite to plasma proteins in systemic circulation.

Metabolism

Ciclesonide is hydrolyzed to its biologically active metabolite by esterase enzymes in the lungs. Enzymology studies using human liver microsomes showed that this compound is predominantly metabolized to hydroxylated inactive metabolites via CYP3A4 isoenzyme-catalyzed reactions.

Additionally, reversible lipophilic fatty acid ester conjugates of the active metabolite have been identified in the lungs.

Elimination

Following oral and intravenous administration, ciclesonide is primarily excreted in feces (67%), indicating that biliary excretion is the main elimination pathway.

Pharmacokinetic/pharmacodynamic relationship:

Patients with bronchial asthma

Ciclesonide does not show pharmacokinetic differences in patients with mild bronchial asthma compared to healthy volunteers.

Elderly patients

According to population pharmacokinetic data, age does not influence systemic exposure to the active metabolite.

Renal or hepatic impairment

Reduced liver function may affect the elimination of corticosteroids. In a study involving patients with hepatic impairment suffering from liver cirrhosis, higher systemic exposure to the active metabolite was observed.

Due to the absence of renal excretion of the active metabolite, studies in patients with renal impairment have not been conducted.

Clinical characteristics.

Indications.

Cyclosedil is indicated for the control of persistent bronchial asthma in adults and children aged 12 years and older.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

In vitro data demonstrate that CYP3A4 is the main enzyme involved in the metabolism of the active metabolite of ciclesonide M1 in humans. In a drug interaction study at steady state between ciclesonide and ketoconazole, a potent CYP3A4 inhibitor, exposure to the active metabolite M1 increased approximately 3.5-fold, while no effect on ciclesonide exposure was observed. Therefore, concomitant use of potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, cobicistat-containing products, ritonavir, or nelfinavir) should be avoided unless the benefit outweighs the increased risk of developing systemic corticosteroid side effects; in such cases, patients should be monitored for the development of systemic corticosteroid side effects.

Special precautions for use.

As with all inhaled corticosteroids, the medicinal product Ciclesidil should be prescribed with caution in patients with active or latent pulmonary tuberculosis, fungal, viral, or bacterial infections, and only if adequate treatment for these conditions is provided.

As with all inhaled corticosteroids, Ciclesidil is not indicated for the treatment of status asthmaticus or other acute asthma attacks requiring intensive therapy.

As with all inhaled corticosteroids, Ciclesidil is not intended for relief of acute symptoms of bronchial asthma, which require the use of short-acting inhaled bronchodilators.

Patients should be advised to always have such rescue medications available.

Systemic effects of inhaled corticosteroids may occur, particularly when administered at high doses over prolonged periods. These effects are considerably less likely than with oral corticosteroids. Potential systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children, decreased bone mineral density, cataract, glaucoma, and less frequently, a range of psychological and behavioral effects such as psychomotor hyperactivity, sleep disturbances, anxiety, depression, or aggression (especially in children). Therefore, it is important that the dose of inhaled corticosteroid be reduced to the lowest dose at which effective control of bronchial asthma is maintained.

Children

In children receiving long-term treatment with inhaled corticosteroids, regular monitoring of growth is recommended. If growth retardation occurs, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid to the lowest dose at which effective control of asthma symptoms is maintained, if possible. Additionally, referral of the patient to a pediatric pulmonologist for evaluation may be appropriate.

Liver function impairment

Data on the use of the drug in patients with severe hepatic impairment are lacking. In patients with severe liver dysfunction, increased drug exposure is expected; therefore, monitoring for potential systemic effects is necessary.

Adrenal gland function impairment

The benefits of using inhaled ciclesonide should minimize the need for oral steroids. However, in patients switched from oral steroid therapy, there remains a risk of adrenal gland dysfunction for a prolonged period after transition to inhaled ciclesonide. The possibility of developing related symptoms may persist for some time. These patients may require specialized consultation to assess the degree of adrenal dysfunction prior to elective procedures. The potential for residual adrenal dysfunction should always be considered in emergency (medical or surgical) and elective situations that may cause stress, and appropriate corticosteroid therapy should be taken into account.

Switching patients previously treated with oral corticosteroids

Switching patients dependent on oral corticosteroids to inhaled ciclesonide and their subsequent management requires particular caution, as recovery of adrenal cortex function suppressed by long-term systemic steroid therapy may take a considerable time.

In patients who have received systemic steroid therapy for prolonged periods or at high doses, adrenal cortex function may be suppressed. In such patients, adrenal cortex function should be monitored regularly, and systemic steroids should be tapered cautiously.

Approximately one week after initiating inhaled ciclesonide, gradual discontinuation of systemic steroids can begin, reducing the dose by 1 mg of prednisolone per week (or equivalent). For maintenance doses of prednisolone exceeding 10 mg daily, a more significant reduction over weekly intervals may be appropriate, provided caution is exercised.

Some patients may experience malaise during withdrawal, with unusual symptoms despite preserved or even improved respiratory function. Patients should be advised to continue inhaled ciclesonide therapy and to continue tapering systemic steroids unless objective signs of adrenal insufficiency are present.

Patients switched from oral steroids who still have impaired adrenal cortex function should carry an alert card indicating the need for additional systemic steroid therapy during periods of stress, such as acute asthma exacerbations, chest infections, severe concomitant illnesses, surgery, or trauma.

Switching from systemic steroid therapy to inhaled therapy may sometimes unmask allergic conditions such as allergic rhinitis or eczema previously controlled by the systemic agent.

Paradoxical bronchospasm with immediate increase in wheezing or other bronchoconstrictive symptoms after drug administration should be treated with a short-acting inhaled bronchodilator, which usually provides rapid relief. The patient should be evaluated, and treatment with Ciclesidil should be continued only if, after careful assessment, the expected benefit outweighs the potential risk. Consideration should be given to the correlation between the severity of bronchial asthma and general susceptibility to acute bronchial reactions (see section "Adverse reactions").

The patient's inhaler technique should be checked regularly to ensure proper coordination between actuation of the inhaler and inhalation, ensuring optimal drug delivery to the lungs.

Concomitant therapy with ketoconazole or other potent CYP3A4 inhibitors, including medicinal products containing cobicistat, may increase the risk of systemic adverse reactions. Such combinations should be avoided unless the benefit outweighs the increased risk of systemic adverse reactions associated with corticosteroid use (see section "Interaction with other medicinal products and other forms of interaction"). In such cases, patients should be monitored for the development of systemic adverse reactions associated with corticosteroid use.

Excipients. The medicinal product contains 4.7 mg of alcohol (ethanol) per dose. The amount of alcohol in one dose of this medicinal product is equivalent to less than 1 ml of beer or wine. This small amount of alcohol has no noticeable effects.

Use during pregnancy or breastfeeding.

Fertility and pregnancy

Adequate and well-controlled studies in pregnant women have not been conducted.

Animal reproductive toxicity studies have shown that glucocorticoids can cause congenital malformations (cleft palate, skeletal abnormalities).

However, these experimental animal findings are unlikely to be relevant to humans when the drug is used at recommended inhaled doses.

In two 12-month dog studies, treatment-related ovarian effects (atrophy) were observed at the maximum dose. These effects occurred at systemic exposure levels 5.27–8.34 times higher than those at a daily dose of 160 mcg. The significance of these findings for humans is unknown.

Animal studies with other glucocorticoids have shown that pharmacological doses of glucocorticoids during pregnancy may increase the risk of intrauterine growth retardation, cardiovascular and/or metabolic disorders in adulthood, and/or irreversible changes in glucocorticoid receptor density, neurotransmitter metabolism, and behavior. The relevance of these data to humans receiving inhaled ciclesonide is unknown.

As with other glucocorticosteroids, ciclesonide should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. The lowest effective dose of ciclesonide that provides adequate control of bronchial asthma symptoms should be used.

Infants born to mothers who received corticosteroids during pregnancy should be carefully monitored for signs of adrenal insufficiency.

Breastfeeding

It is unknown whether ciclesonide passes into breast milk. The use of ciclesonide in breastfeeding women should be considered only if the expected benefit to the mother outweighs any potential risk to the infant.

Effect on ability to drive and use machines.

Ciclesidil has no effect or a negligible effect on the ability to drive and use machinery.

Dosage and Administration

The medicinal product is intended for inhalation use only.

Dosage

Dosage recommendations for adults and children aged 12 years and older

The recommended dose of Cixodil is 160 mcg once daily, which provides control of bronchial asthma in most patients. In patients with severe bronchial asthma and during reduction or withdrawal of oral corticosteroids, a higher dose may be used—up to 640 mcg per day (320 mcg twice daily) (see section "Pharmacological Properties"). The dose of inhaled ciclesonide should be individualized according to the severity of the disease.

Improvement in symptoms with Cixodil occurs within 24 hours of starting treatment. After achieving control, the dose of Cixodil should be individually adjusted and gradually reduced to the lowest effective dose required to maintain adequate control of bronchial asthma.

A reduction to 80 mcg once daily may be an effective maintenance dose for some patients.

Cixodil is preferably administered in the evening, although morning administration of ciclesonide has also demonstrated efficacy. The final decision on whether to administer the drug in the morning or evening should be left to the physician's discretion.

Patients with severe bronchial asthma are at increased risk of acute exacerbations and should undergo regular assessment of asthma control, including lung function tests. An increased frequency of using short-acting bronchodilators to relieve asthma symptoms indicates worsening asthma control. If a patient finds treatment with a short-acting bronchodilator ineffective or feels the need to use more inhalations than usual, medical advice should be sought. In such cases, the patient should be reassessed and consideration given to intensifying anti-inflammatory therapy (e.g., temporarily increasing the dose of Cixodil (see section "Pharmacological Properties") or initiating a course of oral corticosteroids). Treatment of severe asthma exacerbations should be managed according to standard procedures.

To meet individual patient needs—for example, if it is difficult to coordinate pressing the inhaler valve with inhalation—Cixodil can be used with the AeroChamber spacer device with valve Plus Flow-Vu.

Elderly patients and patients with renal or hepatic impairment

Dosage adjustment is not required in elderly patients or in patients with renal or hepatic impairment.

Administration Instructions

Appropriate precautions should be taken before preparing and administering the medicinal product.

Patients should be instructed on the correct use of the inhaler.

If the inhaler is new or has not been used for one week or longer, the first three actuations should be performed into the air. Shaking the canister is not necessary, as it is a solution aerosol.

During inhalation, the patient should sit or stand. The first few times, practice in front of a mirror is recommended until the patient is confident that Cixodil is being used correctly.

Instructions for Correct Use of Cixodil Medicinal Product

The following instructions must be carefully followed.

Proper inhaler technique ensures that the correct amount of CiksoDil medication reaches the lungs each time the inhaler is used. The physician should regularly check the patient's inhalation technique to ensure optimal treatment efficacy. When the canister is completely empty, the patient will no longer taste the medication and will not hear the propellant being released.

If the patient experiences wheezing or chest tightness after using CiksoDil, the following steps should be taken:

• Do not perform any further inhalations;
• Use another inhaler prescribed for relief of breathing difficulties;
• Seek immediate medical assistance.

In case of overdose

The medication must be used exactly as directed in the instructions or as prescribed by the physician. Do not increase or decrease the dose without consulting a doctor.

In case of a missed inhalation

If an inhalation has been missed, it should be taken as soon as possible, following the instructions described above.

Do not take a double dose to compensate for a missed dose.

In case of discontinuation of CiksoDil

Even if the patient feels better, do not stop taking the medication without consulting a physician.

If the patient decides to discontinue treatment with this medication, the physician must be informed immediately.

Additional instructions for handling the medication prior to use

As with most pressurized inhalation medications, the therapeutic effect of this medication may be reduced when the canister is cold. However, CiksoDil delivers a stable dose within a temperature range of -10 °C to 40 °C.

If the inhaler has been significantly cooled before use, remove it from the plastic holder and warm it in the hands for several minutes. Under no circumstances should other heating methods be used to warm the inhaler.

Any unused medication or waste material must be disposed of in accordance with local regulations.

Children

CiksoDil is not recommended for use in children under 12 years of age.

The safety and efficacy of this medication in children from birth to 12 years of age have not yet been established. Sufficient data are lacking.

Overdose

Acute

Inhalation of a single dose of 2880 mcg of ciclesonide in healthy volunteers was well tolerated. The likelihood of acute toxic effects following an overdose of inhaled ciclesonide is low. After acute overdose, specific treatment is not required.

Chronic

No clinical signs of adrenal suppression were observed after prolonged administration of 1280 mcg of ciclesonide. However, if the recommended dose is exceeded over a very long period, some degree of adrenal suppression cannot be ruled out. Monitoring of adrenal function may be necessary.

Adverse reactions.

In clinical studies, adverse reactions were observed in 5% of patients using the ciclesonide aerosol inhaler at doses ranging from 40 to 1280 mcg per day. In most cases, the reactions were mild and did not require discontinuation of treatment with the ciclesonide aerosol inhaler.

* Same or lower frequency compared to placebo.

** Palpitations were observed during clinical trials in cases of concomitant use with medicinal products that may cause adverse effects on heart rhythm (e.g., theophylline or salbutamol).

Paradoxical bronchospasm may occur immediately after inhalation and may be a non-specific acute reaction to any inhaled medicinal product. It may be related to the active substance, excipients, or cooling due to evaporation when using pressurized metered-dose inhalers. In severe cases, discontinuation of Cixodil should be considered.

Systemic effects of inhaled corticosteroids may occur, particularly when administered at high doses over prolonged periods. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children, decreased bone mineral density, cataract, and glaucoma (see also section "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

No special storage conditions required. Do not expose to temperatures above 50 °C.

Keep out of reach and sight of children.

The canister is under pressure; do not pierce. Do not break or throw into fire, even when empty.

Packaging.

80 mcg/dose:

The inhaler consists of an aluminum pressurized canister, hermetically sealed with a metering valve, and a polypropylene mouthpiece and dust cap in green color.

160 mcg/dose:

The inhaler consists of an aluminum pressurized canister, hermetically sealed with a metering valve, and a polypropylene mouthpiece and dust cap in violet color.

320 mcg/dose:

The inhaler consists of an aluminum pressurized canister, hermetically sealed with a metering valve, and a polypropylene mouthpiece and dust cap in red color.

120 doses per inhaler; 1 inhaler per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Djenetik S.p.A.

Manufacturer's address and location of operations.

Quartiere Canfora, 84084 Fisciano, Italy