Alvesco^® (Aerosol) Instructions for Use

Marketing Authorization Holder

AstraZeneca AB (Sweden)

Manufactured By

3M Health Care, Limited (United Kingdom)

Quality Control Release

TAKEDA, GmbH (Germany)

ATC Code

R03BA08 (Ciclesonide)

Active Substance

Ciclesonide (Rec.INN registered by WHO)

Dosage Forms

	Alvesco®	Metered dose inhalation aerosol 40 mcg/1 actuation: canisters of 5 ml (60 actuations) or 8 ml (120 actuations) with a metering valve and mouthpiece
		Metered dose inhalation aerosol 80 mcg/1 actuation: canisters of 5 ml (60 actuations) or 8 ml (120 actuations) with a metering valve and mouthpiece
		Metered dose inhalation aerosol 160 mcg/1 actuation: canisters of 5 ml (60 actuations) or 8 ml (120 actuations) with a metering valve and mouthpiece

Dosage Form, Packaging, and Composition

Metered dose inhalation aerosol in the form of a colorless transparent solution.

Excipients : norflurane (HFA-134a) – 54.51 mg, ethanol – 4.74 mg.

5 ml (60 actuations) – aluminum canisters (1) with a metering valve and a mouthpiece with a protective cap – cardboard packs.
8 ml (120 actuations) – aluminum canisters (1) with a metering valve and a mouthpiece with a protective cap – cardboard packs.

Metered dose inhalation aerosol in the form of a colorless transparent solution.

Excipients : norflurane (HFA-134a) – 54.46 mg, ethanol – 4.74 mg.

5 ml (60 actuations) – aluminum canisters (1) with a metering valve and a mouthpiece with a protective cap – cardboard packs.
8 ml (120 actuations) – aluminum canisters (1) with a metering valve and a mouthpiece with a protective cap – cardboard packs.

Metered dose inhalation aerosol in the form of a colorless transparent solution.

Excipients : norflurane (HFA-134a) – 54.37 mg, ethanol – 4.73 mg.

5 ml (60 actuations) – aluminum canisters (1) with a metering valve and a mouthpiece with a protective cap – cardboard packs.
8 ml (120 actuations) – aluminum canisters (1) with a metering valve and a mouthpiece with a protective cap – cardboard packs.

Clinical-Pharmacological Group

Inhaled corticosteroids

Pharmacotherapeutic Group

Topical glucocorticosteroid

Pharmacological Action

Glucocorticosteroid for topical use by inhalation. Ciclesonide exhibits low affinity for glucocorticoid receptors.

After inhalation, it is converted in the lungs by enzymes into the main metabolite (des-ciclesonide, C21-desmethylpropionylciclesonide), which has pronounced anti-inflammatory activity and is therefore considered the active metabolite.

Ciclesonide suppresses inflammatory reactions in the airways and thus alleviates the symptoms of bronchial asthma and improves lung function.

Pharmacokinetics

Absorption

Oral or intravenous administration of radiolabeled ciclesonide showed that the extent of absorption is 24.5%.

When the drug is taken orally, the bioavailability of both ciclesonide and the active metabolite is negligible (<0.5% for ciclesonide, and <1% for the metabolite) due to the significant influence of presystemic metabolism.

The accumulation of ciclesonide in the lungs in healthy patients is over 50%.

According to this figure, the systemic bioavailability for the active metabolite after an inhalation dose is over 50%.

Since the bioavailability of the active metabolite when ciclesonide is taken orally is less than 1%, the drug taken by inhalation does not have a systemic effect.

Distribution

After intravenous administration to healthy volunteers, ciclesonide is rapidly distributed due to its high lipophilicity.

The V_d averages 2.9 L/kg for ciclesonide and 12.1 L/kg for des-ciclesonide.

The plasma protein binding of ciclesonide is about 99%, and that of the active metabolite is 98-99%.

Metabolism

Ciclesonide is hydrolyzed to a biologically active metabolite by the enzyme esterase in the lungs.

The active metabolite of ciclesonide is mainly metabolized to hydroxylated inactive metabolites via catalysis involving the CYP3A4 isoenzyme.

The clearance of ciclesonide is about 152 L/h and that of des-ciclesonide is about 228 L/h, indicating a high degree of hepatic extraction of the substance.

Excretion

Ciclesonide is excreted mainly in the feces, both after oral administration and after intravenous administration, indicating its predominant excretion in the bile.

Pharmacokinetics in specific patient groups

Patients with renal and hepatic impairment, elderly patients

Dose adjustment is not required in this group of patients.

Since the active metabolite is not excreted by the kidneys, studies in patients with impaired renal function have not been conducted.

In patients with hepatic impairment, a prolonged T_1/2 and a slight increase in the retention time of des-ciclesonide (the active metabolite) in the blood were noted.

Because of this, accumulation of this substance when taking the drug in high doses cannot be ruled out.

Children

The pharmacokinetic parameters of des-ciclesonide are identical for children and adults.

Indications

• Bronchial asthma.

ICD codes

Dosage Regimen

Alvesco^® is used for oral inhalation only.

The drug should be taken daily for a long period of time.

Alvesco^® is dosed individually.

The initial dose should be selected depending on the severity of the condition.

When the desired clinical effect is achieved, the dose should be reduced to the minimum necessary to control the manifestations of the disease.

Adults and adolescents over 12 years of age, elderly patients with mild to moderate bronchial asthma the recommended daily dose is from 160 mcg to 640 mcg; a dose of 640 mcg should be divided into 2 doses per day.

For severe bronchial asthma, the dose can be increased to a maximum of 640 mcg 2 times/day daily.

Improvement in the manifestations of the disease occurs within 24 hours after taking Alvesco^®.

It is assumed that the maximum effect of treatment – as with other inhaled corticosteroids – is achieved after 2-3 months of using the drug.

Patients should not stop treatment, even in the absence of symptoms of bronchial asthma.

Elderly patients do not require dose adjustment.

Children over 6 years of age the recommended daily dose is 80-160 mcg once a day or 80 mcg 2 times a day.

Alvesco^® can be used with or without a spacer.

If the use of a spacer is necessary, it is recommended to use the AeroChamberPlus spacer.

Patients with renal or hepatic impairment do not require dose adjustment.

Adults and adolescents constantly taking oral corticosteroids in patients with severe bronchial asthma who are dependent on oral corticosteroid therapy (e.g., prednisolone), the dose of Alvesco^® is 640 mcg 2 times/day.

Transfer of patients from oral corticosteroids to Alvesco^® is possible during remission.

Alvesco^® at a dose of 640 mcg 2 times/day should be used for 10 days in combination with an oral corticosteroid.

The dose of the oral corticosteroid should then be gradually reduced every week to the minimum effective dose, with a reduction in the daily dose of no more than 2.5 mg each time.

Instructions for using the inhaler

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

If the inhaler is new or has not been used for more than one week, the first three valve presses should be performed into the air.

There is no need to shake the canister because it is a solution aerosol.

1. Remove the protective cap from the sprayer and check the mouthpiece inside and out. Make sure it is clean and dry.

2. Turn the inhaler upside down (with the bottom of the canister up), place your index finger on the bottom of the canister, and your thumb under the mouthpiece.

3. Exhale as much as possible. Do not exhale into the inhaler.

4. Place the mouthpiece in your mouth and close your lips around it.

5. Only after you have started to inhale, press the top of the inhaler with your index finger to release the medicine during a slow and deep inhalation.

Take care to ensure that the medicine cannot pass through the space between the lips and the mouthpiece.

6. Hold your breath, remove the mouthpiece from your mouth, and remove your finger from the top of the inhaler.

Continue to hold your breath for approximately 10 seconds or as long as possible.

Exhale slowly through your mouth. Avoid exhaling through the mouthpiece.

It is important not to rush during steps 3-6.

7. If an additional inhalation is needed, wait 30 seconds and repeat steps 3-6.

8. After use, always put the protective cap back on to protect it from dust. Close it tightly and secure it in place.

9. For hygiene purposes

• Regularly clean the mouthpiece inside and out with a dry cloth;
• Using a dry folded cloth, wipe the surface with the small hole from which the medicine comes out;
• Do not use water or any other liquid.

Adverse Reactions

* identical or lower percentage compared to placebo

** palpitations were observed during clinical trials in cases of concomitant use with drugs that may have side effects on heart rhythm (e.g., theophylline or salbutamol).

Paradoxical bronchospasm may occur immediately after inhalation and is a nonspecific acute reaction to any inhaled medicinal product, which may be associated with the active substance, excipients, or cooling due to evaporation of the propellant in the case of metered-dose inhalers.

In most cases, this is a moderately adverse reaction that does not require discontinuation of Alvesco^® treatment and may resolve on its own.

Inhaled corticosteroids can cause systemic effects, especially when used in high doses for a long time.

Possible systemic effects include Cushing’s syndrome and Cushing’s-like symptoms, such as adrenal suppression, growth retardation in children and adolescents, decreased bone density, cataracts, and glaucoma.

This is why it is important that the dose of the inhaled corticosteroid is reduced to the minimum effective dose that allows satisfactory control of the disease symptoms.

Contraindications

• Age under 6 years;
• Hypersensitivity to the components of the drug.

With caution, the drug should be used in patients with active or chronic pulmonary tuberculosis; in patients with bacterial, viral, or fungal infections of the respiratory tract.

Use in Pregnancy and Lactation

Controlled studies in pregnant women have not been conducted.

However, after inhalation of the drug, the concentration of ciclesonide in the blood serum is very low, therefore, the impact on the embryo and potential reproductive toxicity are negligible.

The excretion of ciclesonide or its metabolites in breast milk has not been studied.

Like other inhaled corticosteroids, Alvesco^® can be used during pregnancy and lactation as prescribed by a doctor if the expected therapeutic effect outweighs the risk of possible side effects.

Newborns whose mothers received corticosteroids during pregnancy should be under medical supervision to rule out adrenal hypofunction.

Use in Hepatic Impairment

Patients with hepatic impairment do not require dose adjustment.

Use in Renal Impairment

Patients with renal impairment do not require dose adjustment.

Pediatric Use

Contraindicated for use in children under 6 years of age. Children over 6 years of age the recommended daily dose is 80-160 mcg once a day or 80 mcg 2 times a day.

Geriatric Use

Elderly patients do not require dose adjustment.

Special Precautions

Alvesco^® is not indicated for the treatment of status asthmaticus or other acute attacks of bronchial asthma requiring intensive therapeutic measures.

The dose of Alvesco^® may be reduced in patients requiring oral corticosteroids.

For patients transferred from oral corticosteroid therapy to inhalation treatment with Alvesco^®, reduced adrenal cortex function may persist for a significant period of time after the transfer.

The possibility of developing undesirable effects from the use of oral corticosteroids may persist for some time after their discontinuation.

In such cases, it is recommended to monitor the reserve function of the adrenal cortex.

The possibility of residual impairment of adrenal cortex function in a critical situation (therapeutic or surgical) and in other individual cases that may be caused by a stress reaction should always be taken into account, and therefore appropriate corticosteroid treatment should be initiated.

In case of adrenal cortex insufficiency or serious exacerbations, the dose of Alvesco^® should be increased; if necessary, then oral corticosteroids should be used.

In case of infection development, antibiotics should be used.

Paradoxical bronchospasm with increased wheezing and other symptoms of bronchoconstriction that appear immediately after inhalation should be treated with a fast-acting bronchodilator, which usually leads to rapid relief.

The patient should be examined, and therapy with Alvesco^® should be continued only if, after careful consideration, the expected benefit outweighs the possible risk.

The relationship between the severity of asthma and the overall predisposition to acute bronchial reactions should be taken into account.

Transfer of patients taking oral corticosteroids to Alvesco^®

When transferring to Alvesco^® and subsequent management of patients who have been treated with oral corticosteroids, medical supervision is required, because recovery of reduced adrenal function caused by prolonged systemic corticosteroid therapy may take some time.

In patients who have received systemic corticosteroids for a long time or in high doses, suppression of adrenal function may be observed.

The adrenal function of these patients must be monitored regularly, and the dose of systemic corticosteroids should be reduced gradually.

After approximately one week, gradual withdrawal of systemic corticosteroids may be started, reducing their daily dose by 1 mg of prednisolone, or its equivalent.

For a maintenance dose of prednisolone greater than 10 mg daily, a more significant dose reduction over weekly intervals may be appropriate, with caution required.

Some patients may feel unwell during drug withdrawal, despite maintaining or even improving respiratory function.

They should be examined for adrenocortical insufficiency.

When transferring patients from systemic corticosteroids to inhalation therapy, allergic reactions (e.g., allergic rhinitis, eczema) that were previously suppressed by systemic drugs may appear.

In such cases, symptomatic therapy with antihistamines, including topical and local preparations containing corticosteroids, should be carried out.

Use in pediatrics

The use of the drug in children under 6 years of age is contraindicated.

The effect of inhaled corticosteroids with long-term use in children is not fully understood.

The doctor should constantly monitor the growth development of children taking corticosteroids for a long period.

If growth slows down, therapy should be reconsidered with the aim of reducing the dose of the inhaled corticosteroid, if possible, to the minimum effective dose that allows control of bronchial asthma symptoms.

Effect on ability to drive vehicles and operate machinery

There are no data on the effect of the drug on the ability to drive vehicles and operate machinery.

Overdose

Acute overdose

Symptoms inhalation of a single dose of 2880 mcg of ciclesonide was well tolerated in healthy volunteers.

The possibility of acute toxic effects following an overdose of inhaled ciclesonide is low.

Increased dryness of the oral and pharyngeal mucosa, sensation of irritation or tickling in the throat, and dysphonia are possible.

Treatment after acute overdose, no specific treatment is necessary.

Chronic overdose

Symptoms after prolonged administration of 1280 mcg of ciclesonide, no clinical signs of adrenal suppression were observed.

However, if the recommended dose is exceeded for an excessively long period of time, some degree of adrenal suppression cannot be ruled out.

Treatment it is recommended to monitor adrenal function. In cases of overdose of Alvesco^® therapy can be continued with a dose sufficient to maintain the therapeutic effect.

Drug Interactions

According to in vitro data, CYP3A4 is the main enzyme involved in the metabolism of the active metabolite of ciclesonide – M1 (des-ciclesonide) in humans.

In drug interaction studies between ciclesonide and ketoconazole, as a strong CYP3A4 inhibitor, the exposure to the active metabolite des-ciclesonide increased approximately 3.5 times, whereas no effect on ciclesonide was noted. Based on this, the concomitant use of potential CYP3A4 inhibitors and ciclesonide should be avoided.

A study of the interaction between ciclesonide and the CYP3A4 substrate erythromycin showed no interaction between them.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

The canister contents are under pressure. The canister must not be opened or heated above 50°C (122°F).

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.