Pulmicort^® (Suspension) Instructions for Use

Marketing Authorization Holder

AstraZeneca AB (Sweden)

Manufactured By

AstraZeneca AB (Sweden)

Packaging and Quality Control Release

ASTRAZENECA AB (Sweden)

Or

ASTRAZENECA INDUSTRIES, LLC (Russia)

Contact Information

AstraZeneca Pharmaceuticals LLC (Russia)

ATC Code

R03BA02 (Budesonide)

Active Substance

Budesonide (Rec.INN WHO registered)

Dosage Forms

	Pulmicort®	Metered dose inhalation suspension 0.5 mg/1 ml: 2 ml containers, 20 pcs.
		Metered dose inhalation suspension 0.25 mg/1 ml: 2 ml containers, 20 pcs.

Dosage Form, Packaging, and Composition

Metered dose inhalation suspension white or almost white, easily resuspendable, sterile.

Excipients: sodium chloride – 8.5 mg, sodium citrate – 0.5 mg, disodium edetate (disodium salt of ethylenediaminetetraacetic acid (dibasic) (disodium EDTA salt)) – 0.1 mg, polysorbate 80 – 0.2 mg, citric acid (anhydrous) – 0.28 mg, purified water – up to 1 ml.

2 ml – low-density polyethylene containers (5) – laminated foil envelopes (4) – cardboard packs with first-opening control.

Clinical-Pharmacological Group

Inhaled corticosteroids

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases; other agents for inhalation administration used for the treatment of obstructive airway diseases; glucocorticoids

Pharmacological Action

Budesonide in recommended doses has an anti-inflammatory effect in the bronchi, reducing the severity of symptoms and the frequency of bronchial asthma exacerbations with fewer side effects than with systemic corticosteroids. It reduces the severity of bronchial mucosal edema, mucus production, sputum formation, and airway hyperreactivity.

It is well tolerated during long-term treatment and does not have mineralocorticoid activity. A dose-dependent effect on plasma and urine cortisol levels has been shown with Pulmicort^®. In recommended doses, the drug has a significantly lesser effect on adrenal function than prednisone at a dose of 10 mg, as shown in ACTH tests.

In bronchial asthma and with the use of inhaled corticosteroids, growth retardation may occur. Studies involving children and adolescents receiving budesonide therapy for a long time (up to 13 years) have shown that patients reached their expected adult height.

Inhaled budesonide therapy is effective in preventing exercise-induced bronchial asthma.

Clinical studies – COPD exacerbations

Several studies on the use of nebulized budesonide at a dose of 4-8 mg/day have shown efficacy in the treatment of COPD exacerbations.

Clinical studies – bronchial asthma

The efficacy of Pulmicort^® has been evaluated in numerous studies. It has been shown that the drug is effective in the treatment of persistent bronchial asthma in both adults and children, when used 1 or 2 times/day. It has also been shown that inhaled Budesonide is effective in treating and preventing exacerbations of bronchial asthma in children and adults.

Pediatric patient population

Clinical studies – croup

In a number of studies in children with croup, Pulmicort^® was compared with placebo. Below are examples of representative studies evaluating the use of Pulmicort^® for the treatment of children with croup.

Efficacy in children with mild to moderate croup

A randomized, double-blind, placebo-controlled study involving 87 children aged from 7 months to 9 years, hospitalized with a clinical diagnosis of croup, was conducted to determine whether Pulmicort^® suspension improves the assessment of croup symptoms or reduces the duration of hospital stay. Patients received Pulmicort^® suspension at an initial dose of 2 mg or placebo, followed by Pulmicort^® at a dose of 1 mg or placebo every 12 hours.

Pulmicort^® suspension led to a statistically significant reduction in the severity of croup symptoms at 12 hours and 24 hours, as well as 2 hours after administration in a subgroup of patients with a baseline symptom score above 3. The duration of hospital stay was also reduced by 33%.

Efficacy in children with moderate to severe croup

A randomized, double-blind, placebo-controlled study compared the efficacy of Pulmicort^® and placebo in the treatment of croup in 83 infants and children (aged from 6 months to 8 years) hospitalized for croup. Patients received Pulmicort^® suspension 2 mg or placebo every 12 hours for up to 36 hours or until discharge from the hospital. The overall assessment of croup symptoms was performed at 0, 2, 6, 12, 24, 36, and 48 hours after the initial dose. At 2 hours, both the Pulmicort^® group and the placebo group showed a similar reduction in the severity of croup symptoms, with no statistically significant difference between the groups. At 6 hours after the initial dose, a statistically significant reduction in the severity of croup symptoms was observed in the Pulmicort^® suspension group compared to the placebo group, and this improvement was similar at 12 and 24 hours.

Pharmacokinetics

Absorption

After inhalation, Budesonide is rapidly absorbed. In adults, the systemic bioavailability of budesonide after inhalation of Pulmicort^® via a nebulizer is approximately 15% of the total prescribed dose and about 40-70% of the delivered dose. C_max in plasma is reached 30 minutes after the start of inhalation.

Distribution and metabolism

Plasma protein binding averages 90%. The V_d of budesonide is approximately 3 L/kg.

Budesonide undergoes extensive biotransformation (more than 90%) in the liver to form metabolites with low glucocorticoid activity. The glucocorticoid activity of the main metabolites (6β-hydroxy-budesonide and 16α-hydroxyprednisolone) is less than 1% of the glucocorticoid activity of budesonide. Budesonide is metabolized mainly by the CYP3A4 enzyme.

Excretion

Metabolites are excreted in the urine unchanged or in conjugated form. Budesonide has a high systemic clearance (about 1.2 L/min). The pharmacokinetics of budesonide are proportional to the administered dose of the drug.

Pharmacokinetics in special clinical cases

The pharmacokinetics of budesonide in patients with impaired renal function have not been studied.

In patients with liver disease, budesonide exposure may increase.

Indications

• Bronchial asthma requiring corticosteroid therapy for:
  • Maintenance therapy;
  • Treatment of exacerbations when the use of budesonide as an inhalation suspension is justified.
• Chronic obstructive pulmonary disease for:
  • Maintenance therapy;
  • Treatment of exacerbations when the use of budesonide as an inhalation suspension is justified as an alternative to systemic corticosteroids.
• Stenosing laryngotracheitis (croup).

ICD codes

Dosage Regimen

Bronchial asthma

The dose of the drug is selected individually. If the recommended dose does not exceed 1 mg/day, the entire dose of the drug can be taken at one time (as a single dose). If a higher dose is taken, it is recommended to divide it into two doses. For all patients, it is desirable to determine the minimum effective maintenance dose.

Recommended initial dose

Children aged 6 months and older 0.25-0.5 mg/day. If necessary, the dose can be increased to 1 mg/day.

Adults/Elderly patients 1-2 mg/day.

Maintenance treatment dose

Children aged 6 months and older 0.25-2 mg/day.

Adults/Elderly patients 0.5-4 mg/day.

In case of severe exacerbations, the dose may be increased.

If an additional therapeutic effect is needed, an increase in the daily dose of Pulmicort^® can be recommended instead of combining the drug with oral corticosteroids, due to the lower risk of systemic effects.

Onset of effect in maintenance treatment

Improvement in asthma control during maintenance therapy with Pulmicort^® may occur within 3 days after the start of treatment, although the maximum effect may not be achieved for 2-4 weeks.

Patients receiving oral corticosteroids

Discontinuation of oral corticosteroids should be started when the patient’s condition is stable. For 10 days, a high dose of Pulmicort^® should be taken while continuing oral corticosteroids at the usual dose. Subsequently, over the course of a month, the dose of oral corticosteroids should be gradually reduced (for example, by 2.5 mg of prednisone or its equivalent) to the minimum effective dose. In many cases, it is possible to completely discontinue oral corticosteroids.

COPD

COPD maintenance therapy

The dose of the drug is selected individually. If the recommended dose does not exceed 1 mg/day, the entire dose of the drug can be taken at one time (as a single dose). If a higher dose is taken, it is recommended to divide it into two doses. For all patients, it is desirable to determine the minimum effective maintenance dose.

Recommended initial dose

Adults/Elderly patients 1-2 mg/day.

Maintenance treatment dose

Adults/Elderly patients 0.5-4 mg/day.

COPD exacerbations

Adults/Elderly patients the daily dose is 4-8 mg. The dose should be divided into 2-4 doses. Treatment should be continued until clinical improvement is achieved, but for no more than 10 days.

Onset of effect

After inhalation of Pulmicort^® for the treatment of COPD exacerbations, the time to symptom improvement is comparable to that with systemic corticosteroids.

Stenosing laryngotracheitis (croup)

Children aged 6 months and older 2 mg/day.

The dose of the drug can be taken at one time (as a single dose) or divided into two doses of 1 mg with an interval of 30 minutes.

Impaired liver or kidney function

There are no data on the use of budesonide in patients with impaired liver or kidney function. Considering the fact that Budesonide is eliminated by biotransformation in the liver, an increase in drug exposure can be expected in patients with severe cirrhosis.

Determination of the drug dose

* Should be diluted with 0.9% sodium chloride solution to a volume of 2 ml.

Since Pulmicort^®, used as a suspension via a nebulizer, enters the lungs during inhalation, it is important to instruct the patient to inhale the drug through the nebulizer mouthpiece calmly and evenly.

Use of Pulmicort^® with a nebulizer

Pulmicort^® is used for inhalation using an appropriate nebulizer equipped with a mouthpiece and a special mask. The nebulizer is connected to a compressor to create the required air flow (5-8 L/min), the filling volume of the nebulizer should be 2-4 ml.

It is important to inform the patient

• To carefully read the instructions for use of the drug;
• Ultrasonic nebulizers are not suitable for the use of Pulmicort^® suspension;
• Pulmicort^® suspension is mixed with 0.9% sodium chloride solution or with solutions of terbutaline, salbutamol, fenoterol, acetylcysteine, sodium cromoglycate and ipratropium bromide; the diluted suspension should be used within 30 minutes;
• After inhalation, the mouth should be rinsed with water to reduce the risk of oropharyngeal candidiasis;
• To prevent skin irritation, the face should be washed with water after using the mask;
• It is recommended to regularly clean the nebulizer according to the manufacturer’s instructions.

In cases where a child cannot independently inhale through a nebulizer, a special mask is used.

How to use Pulmicort^® with a nebulizer

1. Before use, gently shake the container with a light rotating motion.
2. The container should be held straight upright and opened by turning and tearing off the “wing”.
3. Carefully place the container with the open end into the nebulizer and slowly squeeze out the contents of the container.

The container containing a single dose is marked with a line. If the container is turned over, this line will show a volume equal to 1 ml.

If only 1 ml of suspension needs to be used, the contents of the container are squeezed out until the liquid surface reaches the level marked by the line.

The opened container should be stored in a light-protected place.

The opened container must be used within 12 hours.

Before using the remaining liquid, the contents of the container should be gently shaken with a rotating motion.

Note

1. After each inhalation, the mouth should be rinsed with water.
2. If the patient uses a mask, it is necessary to ensure that the mask fits snugly to the face during inhalation. After inhalation, the face should be washed.

Cleaning

The nebulizer chamber, mouthpiece, or mask should be cleaned after each use.

The nebulizer chamber, mouthpiece, or mask are washed with warm water using a mild detergent, or according to the manufacturer’s instructions.

The nebulizer should be rinsed well and dried by connecting the chamber to the compressor or inlet air valve.

Adverse Reactions

The frequency of adverse effects is presented as follows: common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000), including isolated reports.

Up to 10% of patients taking the drug may experience the side effects listed below.

Respiratory system common – oropharyngeal candidiasis, moderate irritation of the pharyngeal mucosa, cough, hoarseness, dry mouth, pneumonia (in patients with COPD); rare – bronchospasm.

Immune system rare – angioedema, immediate and delayed hypersensitivity reactions, including rash, contact dermatitis, urticaria, angioedema, bronchospasm and anaphylactic reaction.

Nervous system rare – nervousness, excitability, depression, behavioral disorders.

Eye disorders very rare – cataract, glaucoma (systemic effect).

Digestive system rare – nausea.

Skin and subcutaneous tissue disorders rare – skin bruising.

Laboratory parameters very rare – decreased bone mineral density (systemic effect).

Given the risk of oropharyngeal candidiasis, the patient should thoroughly rinse the mouth with water after each inhalation of the drug.

In rare cases, symptoms caused by the systemic action of corticosteroids may occur, including adrenal hypofunction and growth retardation in children. The severity of these symptoms likely depends on the dose of the drug, duration of therapy, concomitant or previous corticosteroid therapy, and individual sensitivity.

Cases of facial skin irritation when using a nebulizer with a mask have been reported. To prevent irritation, the face should be washed with water after using the mask.

Contraindications

• Children under 6 months of age;
• Hypersensitivity to budesonide.

With caution pulmonary tuberculosis (active or inactive form), fungal, viral or bacterial respiratory tract infections, liver cirrhosis, pregnancy, breastfeeding period.

Use in Pregnancy and Lactation

Pregnancy

Observation of pregnant women who took Budesonide did not reveal fetal developmental abnormalities, however, the risk of their development cannot be completely excluded, therefore, during pregnancy, due to the possibility of worsening bronchial asthma, the minimum effective dose of budesonide should be used.

Lactation period

Budesonide passes into breast milk, but no effects on the child have been observed when using Pulmicort^® in therapeutic doses. Pulmicort^® can be used during breastfeeding.

Use in Hepatic Impairment

The drug should be prescribed with caution to patients with liver cirrhosis.

Use in Renal Impairment

There are no data on the use of budesonide in patients with impaired renal function.

Pediatric Use

Contraindicated in children under 6 months of age.

Special Precautions

Budesonide is not intended for the rapid relief of acute asthma attacks, when the use of short-acting inhaled bronchodilators is required.

In case of exacerbation, the dose of Pulmicort^® can be increased or short-term additional therapy can be prescribed.

As with other inhalation therapy, paradoxical bronchospasm with immediate worsening of wheezing after administration of Pulmicort^® may occur. In such a case, inhalation therapy with budesonide should be discontinued immediately, the patient’s condition should be assessed, and, if necessary, alternative therapy should be prescribed.

Fungal infections of the oral cavity may occur with the use of inhaled corticosteroids. If such an infection develops, the use of appropriate antifungal agents may be required, and in some patients, discontinuation of inhaled corticosteroids. To reduce the risk of developing fungal infection of the oropharynx, the patient should be instructed to rinse the mouth thoroughly with water after each inhalation of the drug.

Concomitant administration of budesonide with ketoconazole, itraconazole, or other potent CYP3A4 inhibitors should be avoided. If budesonide and ketoconazole or other potent CYP3A4 inhibitors have been prescribed, the time between drug administrations should be increased to the maximum possible.

Due to the possible risk of adrenal function impairment, special attention is required for patients who are transferred from oral corticosteroids to Pulmicort^®. Special attention is also required for patients who have been taking high doses of corticosteroids or have been receiving the maximum recommended doses of inhaled corticosteroids for a long time. In stressful situations, such patients may show signs and symptoms of adrenal insufficiency. During stress or in cases of surgery, additional therapy with systemic corticosteroids is recommended.

Special attention is required for patients who are transferred from systemic to inhaled corticosteroids (Pulmicort^®) or when impairment of pituitary-adrenal function can be expected. In such patients, the dose of systemic corticosteroids should be reduced with particular caution and hypothalamic-pituitary-adrenal function should be monitored. Patients may also require supplementation with oral corticosteroids during periods of stress, such as trauma, surgery, etc.

When switching from oral corticosteroids to Pulmicort^®, patients may experience previously observed symptoms, such as muscle pain or joint pain. In such cases, a temporary increase in the dose of oral corticosteroids may be needed. In rare cases, symptoms such as feeling tired, headache, nausea, and vomiting, indicating systemic corticosteroid insufficiency, may be observed.

Replacement of oral corticosteroids with inhaled corticosteroids sometimes leads to the manifestation of concomitant allergies, such as rhinitis and eczema, which were previously controlled by systemic drugs.

Possible systemic effects include Cushing’s syndrome, cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataracts, glaucoma, and psychological symptoms and behavioral disturbances, including psychomotor hyperactivity, sleep disorders, anxiety, depression, and aggression, especially in children (see the “Adverse Reactions” section). The dose of inhaled corticosteroids should be the lowest that maintains effective control of the disease.

Impaired liver function may affect the elimination of glucocorticoids, causing a decrease in the elimination rate and an increase in systemic exposure. Patients should be warned about possible systemic adverse reactions.

Clinical studies and meta-analyses have shown that the use of inhaled corticosteroids in the maintenance therapy of COPD may lead to an increased risk of pneumonia. Physicians should be aware of the possibility of pneumonia development in patients with COPD, since the clinical signs of pneumonia and disease exacerbation often coincide.

Visual disturbances may occur with systemic and local use of corticosteroids. If a patient develops symptoms such as blurred vision or other visual disturbances, the need for referral to an ophthalmologist should be considered to assess possible causes, which may include cataract, glaucoma, or rare conditions such as central serous chorioretinopathy (CSCR), noted after systemic and local corticosteroid use.

Use in Pediatrics

In children and adolescents receiving corticosteroid treatment (regardless of the route of administration) for a prolonged period, it is recommended to monitor growth parameters regularly. If growth retardation occurs, therapy should be reviewed to reduce the dose of the inhaled corticosteroid, if possible, to the lowest dose that maintains effective control of bronchial asthma. The benefit-risk ratio of glucocorticoid therapy and the possible risk of growth retardation should be carefully evaluated. Additionally, it is recommended to refer the patient to a pediatric pulmonologist.

The use of budesonide at doses up to 400 mcg/day in children over 3 years of age did not lead to systemic effects. Biochemical signs of the systemic effect of the drug may occur at doses from 400 to 800 mcg/day. At doses exceeding 800 mcg/day, systemic effects of the drug occur frequently. Systemic effects may occur with the use of any inhaled corticosteroids, especially when used in high doses for a long period. The likelihood of developing such symptoms is significantly lower with inhaled glucocorticoid therapy than with oral corticosteroids.

Effect on Ability to Drive and Use Machines

Pulmicort^® does not affect the ability to drive a car or operate other machinery.

Overdose

Acute overdose does not produce clinical manifestations.

With long-term use of the drug in doses significantly exceeding the recommended ones, development of systemic corticosteroid effects in the form of hypercorticism and adrenal suppression is possible.

Drug Interactions

No interaction of budesonide with other drugs used in the treatment of bronchial asthma has been observed.

Concomitant administration of ketoconazole (at a dose of 200 mg once daily) increases the plasma concentration of budesonide (taken orally at a dose of 3 mg once daily) by an average of 6 times. When ketoconazole was taken 12 hours after budesonide intake, the plasma concentration of the latter increased by an average of 3 times. Information on such interaction with inhaled budesonide is lacking, but it is assumed that an increase in budesonide plasma concentration should be expected in this case as well. If it is necessary to take ketoconazole and budesonide, the time between drug administrations should be increased to the maximum possible. The possibility of reducing the budesonide dose should also be considered.

Another potential CYP3A4 inhibitor, itraconazole, also significantly increases the plasma concentration of budesonide.

Preliminary inhalation of beta-adrenergic agonists dilates the bronchi, improves the delivery of budesonide to the airways, and enhances its therapeutic effect.

Phenobarbital, phenytoin, and rifampicin reduce the effectiveness of budesonide when used concomitantly (due to induction of microsomal oxidation enzymes).

Methandrostenolone and estrogens enhance the effect of budesonide.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date printed on the package.

The drug in containers must be used within 3 months after opening the foil envelope.

An opened container must be used within 12 hours. Containers should be stored in the foil envelope to protect them from light.

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.