Symbicort^® Rapihaler (Aerosol) Instructions for Use

Marketing Authorization Holder

AstraZeneca AB (Sweden)

Manufactured By

AstraZeneca Dunkerque Production (France)

Packaging and Quality Control Release

ASTRAZENECA DUNKERQUE PRODUCTION (France)

Contact Information

AstraZeneca Pharmaceuticals LLC (Russia)

ATC Code

R03AK07 (Formoterol and budesonide)

Active Substances

Budesonide (Rec.INN registered by WHO)

Formoterol (Rec.INN registered by WHO)

Dosage Forms

	Symbicort® Rapihaler	Metered dose inhalation aerosol 80 mcg+4.5 mcg/1 dose: inhaler 120 doses
		Metered dose inhalation aerosol 160 mcg+4.5 mcg/1 dose: inhaler 120 doses

Dosage Form, Packaging, and Composition

Metered dose inhalation aerosol; the canister contents are a white solid residue, free from visible inclusions, formed after the propellant evaporates.

Excipients : povidone K25 – 0.75 mcg, macrogol 1000 – 223.8 mcg, apaphluran 227 – up to 74.6 mg.

8 ml (120 doses) – inhalers** (1) – laminated aluminum foil bags (1) with desiccant – cardboard packs with first-opening control.

Metered dose inhalation aerosol; the canister contents are a white solid residue, free from visible inclusions, formed after the propellant evaporates.

Excipients : povidone K25 – 0.75 mcg, macrogol 1000 – 223.8 mcg, apaphluran 227 – up to 74.6 mg.

8 ml (120 doses) – inhalers** (1) – laminated aluminum foil bags (1) with desiccant – cardboard packs with first-opening control.

* For quality control of the medicinal product, the term “dose” corresponds to one release of the medicinal product. The therapeutic dose is 2 releases of the product.
** Inhaler: a canister placed inside a red dispensing device with a white mouthpiece and a grey dose counter; a grey protective cap is attached to the dispensing device via a holder.
Primary packaging: the contents are in a metal canister equipped with a plastic metering cap. There is no corrosion or significant defects on the external and internal surfaces of the canister and valve.

Clinical-Pharmacological Group

Combined bronchodilator drug – selective beta₂-adrenomimetic + topical glucocorticosteroid

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases; adrenergic agents for inhalation administration; adrenergic agents in combination with glucocorticoids or other drugs, except anticholinergic agents

Pharmacological Action

Symbicort^® Rapihaler contains budesonide and formoterol, which have different mechanisms of action and exhibit an additive effect in obstructive airway diseases.

The inhaler contains a suspension for inhalation. When the top of the inhaler is pressed, a certain amount of suspension is released at high speed. If the patient inhales simultaneously with the release of the drug, it enters the airways directly.

Mechanism of action

Budesonide

Budesonide is a glucocorticoid that exerts a local anti-inflammatory effect. The exact mechanism of the anti-inflammatory action of glucocorticosteroids in obstructive lung diseases is not fully understood.

The specific activity of budesonide, assessed by its affinity for glucocorticoid receptors, is 15 times higher than that of prednisolone. An apparent effect of budesonide (reduction of cortisol concentration to 80% of the normal level) was established for a dose of 800 mcg; a significant decrease in cortisol concentration was noted in some patients.

Results from a long-term study indicate that children and adolescents receiving inhaled budesonide in low or medium doses achieve normal growth in adulthood. However, the possibility of a transient growth retardation of approximately 1 cm during the first year of treatment should be considered.

Formoterol

Formoterol, presented as a racemic mixture, is a selective stimulant of β₂-adrenergic receptors, exerting a relaxing effect on bronchial smooth muscle in patients with reversible airway obstruction.

The action of formoterol begins rapidly (within 1-3 minutes after inhalation) and lasts for 12 hours after a single inhalation.

Clinical efficacy

Bronchial asthma

The therapeutic equivalence of Symbicort^® Rapihaler and Symbicort^® Turbuhaler^® was established in two studies of the efficacy and safety of these drugs in medium and high doses in patients with bronchial asthma aged 6 to 79 years. This equivalence was confirmed by the results of a long-term study, which indicate that the safety profile and tolerability of Symbicort^® Rapihaler and Symbicort^® Turbuhaler^® are comparable.

Clinical study results showed that the addition of formoterol to budesonide reduced the severity of asthma symptoms, improved lung function, and reduced the frequency of exacerbations.

When Symbicort^® Rapihaler was prescribed as maintenance therapy for adult patients, its effect on lung function was similar to that of budesonide and formoterol used as separate drugs in the form of a powder for inhalation, and superior to the effect of budesonide used as monotherapy in adults and children. In all these types of therapy, a short-acting β₂-adrenergic agonist was additionally used as needed. No reduction in the anti-asthmatic effect over time was noted.

COPD (chronic obstructive pulmonary disease)

The efficacy and safety of Symbicort^® Rapihaler in patients with moderate to severe COPD (pre-bronchodilator forced expiratory volume in the first second (FEV₁) ≤50% of predicted) were studied in two studies lasting 12 and 6 months (studies 001 and 002).

Both studies investigated the efficacy of Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose compared with placebo and formoterol Turbuhaler^® 4.5 mcg; study 002 also compared the efficacy of Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose with budesonide 160 mcg in the form of a metered dose inhalation aerosol. The drugs were administered as 2 inhalations 2 times/day. Out of 1964 and 1704 patients with COPD, mostly severe, randomized in these studies, 494 and 277 patients received Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose. The average age of patients in these studies was 63 years, before treatment the FEV₁ value was, on average, 1.04-1.05 L, or 34% of the predicted value.

Study 001. In this study, the drug’s efficacy over 12 months was assessed using the primary efficacy variable, defined as the change in the mean FEV₁ value, which was assessed before inhalation and 1 hour after drug administration throughout the treatment period relative to baseline values.

During therapy with Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose, a significant increase in the FEV₁ value measured 1 hour before inhalation was noted by 0.04 L (p=0.008) compared with formoterol therapy, and by 0.09 L (p<0.001) compared with placebo. Throughout the treatment period, the Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose therapy group showed a significant increase in FEV₁ measured 1 hour after inhalation by 0.03 L (p=0.023) compared with formoterol and by 0.18 L (p<0.001) compared with placebo.

In a subgroup of patients (n=491), serial FEV₁ measurements were performed over 12 hours. At the end of the treatment period, the onset of bronchodilation (increase in FEV₁ by more than 15%) in patients receiving Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose (n=121) was observed, on average, 5 minutes after inhalation. The maximum increase in FEV₁ was observed approximately 2 hours after inhalation, and a clinically significant improvement in this indicator persisted for 12 hours.

The use of Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose significantly reduced the number of severe exacerbations: by 37% (p<0.001) compared with placebo and by 25% (p=0.004) compared with formoterol (a severe exacerbation was defined as a worsening of COPD requiring oral glucocorticosteroids and/or hospitalization). Compared with placebo, the time to the first severe COPD exacerbation when using Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose significantly increased, with the immediate risk of severe COPD exacerbation reduced by 26% (p=0.009). During therapy with Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose, a statistically significant improvement in patients’ quality of life was noted compared with placebo (assessment by the St. George’s Hospital Respiratory Questionnaire; -2.39 units; p=0.006).

Study 002. In this study, the drug’s efficacy over 6 months was assessed using the primary efficacy variable, defined as the change in the mean FEV₁ value, which was assessed before inhalation and 1 hour after drug administration throughout the treatment period relative to baseline values.

During therapy with Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose, a significant increase in the FEV₁ value measured 1 hour before inhalation was noted by 0.04 L (p=0.026) compared with formoterol therapy, and by 0.08 L (p<0.001) compared with placebo and budesonide. The Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose therapy group showed a significant increase in FEV₁ measured 1 hour after inhalation by 0.04 L (p=0.039) compared with formoterol and by 0.17 L (p<0.001) compared with placebo and budesonide.

The power of study 002 was insufficient to assess the effect on the frequency of severe COPD exacerbations. The values obtained in the treatment groups are consistent with the results of study 001, although the differences did not reach statistical significance. Thus, the number of exacerbations when taking Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose decreased by 20% compared with placebo and formoterol.

In a subgroup of patients (n=618), serial FEV₁ measurements were performed over 12 hours. At the end of the treatment period, the onset of bronchodilation (increase in FEV₁ by more than 15%) in patients receiving Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose (n=101) was observed, on average, 5 minutes after inhalation. The maximum increase in FEV₁ was observed approximately 2 hours after inhalation, and a clinically significant improvement in this indicator persisted for 12 hours. During therapy with Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose, a statistically significant improvement in patients’ quality of life was noted compared with placebo, budesonide, and formoterol (assessment by the St. George’s Hospital Respiratory Questionnaire): placebo -3.12 units (p=0.003), budesonide -2.42 units (p=0.024), formoterol -2.56 units (p=0.017).

Pharmacokinetics

The pharmacokinetic parameters of budesonide and formoterol when administered by inhalation as separate drugs and when using Symbicort^® Rapihaler were comparable. No signs of pharmacokinetic interaction between budesonide and formoterol were noted.

Absorption

For budesonide when used in the combined product, the AUC was somewhat larger, absorption occurred faster, and the C_max in plasma was higher. For formoterol when used in the combined product, the C_max in plasma was somewhat lower.

Budesonide

When budesonide is used in the form of a metered dose inhalation aerosol (Rapihaler), approximately 25-30% of the metered dose reaches the lungs. After inhalation of a single dose of budesonide 800 mcg, the C_max in blood plasma reaches 4 nmol/L within 30 minutes. The systemic bioavailability of budesonide delivered via metered dose inhalation aerosol (Rapihaler) is approximately 38% of the metered dose.

The pharmacokinetic parameters of budesonide are dose-dependent when used in clinically significant doses.

Formoterol

Formoterol delivered by inhalation is rapidly absorbed, with C_max in blood plasma reached within 10 minutes after inhalation.

Approximately 21-37% of the metered dose reaches the lungs when using the metered dose inhalation aerosol (Rapihaler). Systemic bioavailability after inhalation is approximately 46% of the metered dose.

Distribution

Budesonide

The V_d of budesonide is approximately 3 L/kg. Binding to plasma proteins averages 90%.

Formoterol

The V_d of formoterol is approximately 4 L/kg. Binding to plasma proteins averages 50%.

Metabolism

No signs of interaction at the level of metabolism or substitution reactions between budesonide and formoterol were noted.

Budesonide

Budesonide undergoes significant biotransformation (about 90%) during the “first pass” through the liver, forming metabolites with low glucocorticoid activity. The glucocorticoid activity of the main metabolites, 6β-hydroxy-budesonide and 16α-hydroxy-prednisolone, is less than 1% of the glucocorticoid activity of budesonide. The metabolism of budesonide occurs mainly with the participation of the cytochrome P450 isoenzyme CYP3A4.

Formoterol

The metabolism of formoterol occurs through direct glucuronidation and the formation of O-demethylated metabolites. The metabolites are mainly inactive conjugates.

Excretion

Budesonide

Budesonide metabolites are excreted by the kidneys unchanged or in conjugated form. A small amount of unchanged budesonide is found in the urine. In healthy adult volunteers, budesonide has a high systemic clearance (approximately 1.2 L/min). The T_1/2 averages 4 hours after IV administration.

Formoterol

Formoterol is excreted predominantly in metabolized form. 6-10% of the delivered dose is excreted unchanged by the kidneys; approximately 20% of the intravenously administered dose is excreted unchanged by the kidneys. Formoterol has a high systemic clearance (approximately 1.4 L/min). The T_1/2 averages 17 hours.

Pharmacokinetics in special patient groups

The pharmacokinetic parameters when prescribing the combined product of budesonide and formoterol in children have not been studied. However, it is assumed that the pharmacokinetic parameters of budesonide and formoterol in children do not differ from those in adult patients.

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

The pharmacokinetics of formoterol and budesonide in patients with impaired liver function have not been studied. The excretion of budesonide and formoterol occurs mainly as metabolites, so the elimination of the substances may be slowed in patients with severe liver cirrhosis.

Indications

• Bronchial asthma, insufficiently controlled by inhaled glucocorticosteroids in low doses and short-acting β₂-adrenergic stimulants, when combination therapy with inhaled glucocorticosteroids and long-acting β₂-adrenergic stimulants is appropriate;
• Symptomatic treatment in patients with COPD with post-bronchodilator FEV₁<70% of predicted and with a history of exacerbations, despite regular bronchodilator therapy.

ICD codes

Dosage Regimen

For inhalation use.

Symbicort^® Rapihaler is delivered directly to the lungs after inhalation, so the patient must be trained in the correct use of the inhaler (see the subsection “Instructions for using Symbicort^® Rapihaler”).

The patient should be informed about the need to use Symbicort^® Rapihaler regularly, i.e., to continue taking it even in the absence of disease symptoms, to achieve the greatest therapeutic effect.

Bronchial asthma

The dose of Symbicort^® Rapihaler should be regularly monitored by the attending physician, who adjusts it individually depending on the severity of the disease in accordance with current guidelines. The initial dose is selected to achieve effective symptom control. After achieving the desired clinical effect, the dose should be gradually reduced to the minimum dose that allows optimal control of asthma symptoms. Thus, a subsequent transition to therapy with only inhaled glucocorticosteroids may be possible. When discontinuing treatment with Symbicort^® Rapihaler, it is recommended to gradually reduce the dose.

In case of severe bronchial asthma, regular medical supervision is necessary, as life-threatening situations may arise. Patients with severe bronchial asthma have persistent disease symptoms, frequent exacerbations, and peak expiratory flow values are less than 60% of the normal value, vary by more than 30%, and do not normalize despite taking bronchodilators. Such patients are prescribed inhaled glucocorticosteroids in high doses or oral glucocorticosteroids. In case of sudden worsening of symptoms, an increase in the dose of glucocorticosteroids under medical supervision is possible. In this case, an increase in the dose of inhaled glucocorticosteroids should not be achieved by more frequent use of the combination product. In unstable asthma, a transition to therapy with single-ingredient products may be possible.

Recommendations for the use of Symbicort^® Rapihaler in patients receiving oral corticosteroids are provided in the “Special Precautions” section.

Dosage

Bronchial asthma

Patients take a maintenance daily dose of Symbicort^® Rapihaler and, if necessary, a rapid-acting bronchodilator for symptom relief.

Children aged 6 to 11 years

Symbicort^® Rapihaler 80 mcg + 4.5 mcg/dose: 2 inhalations twice daily. The maximum daily dose is 4 inhalations of 80 mcg + 4.5 mcg/dose.

Children aged 12 to 17 years

Symbicort^® Rapihaler 80 mcg + 4.5 mcg/dose: 2 inhalations once or twice daily. In case of worsening symptoms, the dose can be temporarily increased (for no more than 1 week) to 4 inhalations twice daily.

Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose: 2 inhalations once or twice daily. In case of worsening symptoms, the dose can be temporarily increased (for no more than 1 week) to 4 inhalations twice daily.

Adults (18 years and older)

Symbicort^® Rapihaler 80 mcg + 4.5 mcg/dose: 2 inhalations once or twice daily. In case of worsening symptoms, the dose can be increased to 4 inhalations twice daily temporarily or as a maintenance dose.

Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose: 2 inhalations once or twice daily. In case of worsening symptoms, the dose can be temporarily increased to 4 inhalations twice daily temporarily or as a maintenance dose.

Statistical equivalence was established between Symbicort^® Turbuhaler^® and Symbicort^® Rapihaler when using 2 inhalations of 80 mcg + 4.5 mcg/dose or 160 mcg + 4.5 mcg/dose twice daily. However, this equivalence was not confirmed for all dosages.

Patients should be informed about the need to always carry a rapid-acting bronchodilator for relief of attacks. Frequent use of the drug for relief of attacks indicates worsening bronchial asthma and requires therapy adjustment.

COPD

Symbicort^® Rapihaler 160 mcg + 4.5 mcg/dose: 2 inhalations twice daily. The maximum daily dose is 4 inhalations.

Symbicort^® Rapihaler 80 mcg + 4.5 mcg/dose is not used (not registered) for the treatment of COPD.

Use in special patient groups

There are no data on the use of Symbicort^® Rapihaler in patients with impaired liver and kidney function. The elimination of budesonide and formoterol occurs mainly through metabolism in the liver, so increased exposure is possible in patients with severe liver disease. Such patients should be closely monitored.

No dose adjustment is required for elderly patients.

Instructions for using the Symbicort^® Rapihaler

Before starting to use the drug, the patient should carefully read this section.

Inhaler

The inhaler is supplied assembled. The inhaler should not be disassembled into its component parts. If the connection of the inhaler parts becomes loose, they should be secured and the inhaler should continue to be used as prescribed by the doctor.

Preparing the inhaler for use

Before first use, remove the inhaler from the laminated aluminum foil pouch. The pouch can be discarded.

Before using the inhaler for the first time, or if the inhaler has not been used for a week or more, or if the inhaler has been dropped, it must be prepared for use: shake gently and release 2 doses into the air.

How to hold the inhaler correctly when using

Or

Using the inhaler

1. Before each use, shake the inhaler gently.
2. Remove the protective cap from the mouthpiece by pressing on both sides and pulling.
3. Hold the inhaler upright in front of the mouth, placing the thumb (or thumbs of both hands) on the base of the inhaler and the index finger (index fingers) on the top of the inhaler. Then exhale as deeply as possible, place the inhaler mouthpiece between the teeth and close the lips tightly around it.
4. Then take a slow, deep breath through the mouth. At the beginning of the inhalation, press the inhaler’s dosing mechanism to release the drug.
5. After the deep inhalation, hold your breath for about 10 seconds or as long as is comfortable. Then remove the inhaler from the mouth and the finger from the top of the inhaler.
6. Following the doctor’s prescription, take another inhalation – shake the inhaler gently and repeat steps 3-5.
7. Put the protective cap back on the mouthpiece and close it to prevent dust and other contaminants from entering; a quiet click may be heard.
8. Rinse the mouth with water to remove any residual drug.

Cleaning the inhaler

It is necessary to regularly clean the inhaler mouthpiece at least once a week as follows:

1. Remove the protective cap from the mouthpiece.
2. Wipe the mouthpiece inside and out with a clean, dry cloth.
3. Close the mouthpiece with the protective cap.
4. Do not immerse the inhaler in water.
5. Do not disassemble the inhaler into its component parts.

Dose counter

• The arrow of the dose counter on the top of the inhaler indicates the number of doses of the drug remaining in the inhaler.

• After each dose release (during preparation for use and during inhalation), the dose counter reading decreases.
• When the dose counter arrow is in the yellow band, this means that there are approximately 20 doses left in the inhaler.

• It is important to pay attention to the dose counter reading and know how much drug is left in the inhaler. When the dose counter arrow points to 0 (zero), this means that all the drug from this inhaler has been used and the inhaler should be disposed of. The inhaler may not be empty and may remain operational, but when using such an inhaler, the required amount of medication may not be received.

It should be remembered that the medicinal product is intended for individual use. The drug should not be passed on to other persons, even if they have the same symptoms. This could harm them.

Adverse Reactions

With the concomitant use of budesonide and formoterol, no increase in the frequency of adverse reactions was noted. The most common adverse reactions associated with the drug are such pharmacologically expected undesirable effects for beta₂-adrenergic agonists as tremor and palpitations; symptoms are usually of moderate severity and disappear within a few days after starting treatment. During the use of budesonide in COPD, bruising and pneumonia occurred with a frequency of 10% and 6%, respectively, compared with 4% and 3% in the placebo group (p<0.001 and p<0.01, respectively). Since Symbicort^® Rapihaler contains two active substances, budesonide and formoterol, adverse effects may occur during its use, similar in nature and intensity to the effects described for these two drugs when used separately. In clinical studies, respiratory system disorders, mainly bronchitis, nasopharyngitis, sinusitis, viral upper respiratory tract infection, in the group of patients receiving Symbicort^® 160 mcg + 4.5 mcg/dose, were observed in at least 3% of patients and more often than in the placebo group.

Adverse reactions associated with the use of budesonide or formoterol are presented below using preferred terms by system organ class and indicating absolute frequency. The frequency of reactions is presented in the following gradation: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000).

Nervous system disorders common – headache, tremor; uncommon – dizziness; very rare – taste perversion.

Psychiatric disorders uncommon – psychomotor hyperactivity, anxiety, sleep disorder, restlessness, nervousness; very rare – depression, behavioral changes (mainly in children).

Infections and infestations common – oropharyngeal candidiasis.

Immune system disorders immediate and delayed hypersensitivity reactions (e.g., dermatitis, exanthema, urticaria, pruritus, contact eczema, angioedema and anaphylactic reaction).

Metabolism and nutrition disorders very rare – hyperglycemia, hypokalemia, signs and symptoms of systemic glucocorticoid effects (including reduced adrenal cortex function).

Cardiac disorders common – palpitations; uncommon – tachycardia; cardiac arrhythmias (e.g., atrial fibrillation, supraventricular tachycardia, extrasystole); very rare – angina pectoris, blood pressure changes.

Respiratory, thoracic and mediastinal disorders common – cough, hoarseness, mild irritation of the pharyngeal mucosa with swallowing disorders; rare – bronchospasm; very rare – paradoxical bronchospasm.

Musculoskeletal and connective tissue disorders uncommon – muscle cramps, myalgia.

Gastrointestinal disorders uncommon – nausea.

Skin and subcutaneous tissue disorders rare – bruising.

The development of systemic effects of inhaled corticosteroids (adrenal insufficiency, hypercorticism, growth retardation in children and adolescents, cataract, glaucoma, increased intraocular pressure in rare cases) is possible, especially with long-term use of the drug in high doses.

The use of beta₂-adrenergic agonists may lead to an increase in the blood levels of insulin, free fatty acids, glycerol and ketone bodies.

Contraindications

• Hypersensitivity to budesonide, formoterol or excipients included in the drug;
• AV block III degree;
• Initial therapy of status asthmaticus or acute attacks of bronchial asthma and COPD requiring intensive care;
• Children under 6 years of age;
• Children under 12 years of age (for the dosage of 160 mcg + 4.5 mcg/dose).

With caution pulmonary tuberculosis (active or inactive form), fungal, viral or bacterial respiratory tract infections, thyrotoxicosis, pheochromocytoma, diabetes mellitus, reduced adrenal cortex function, uncontrolled hypokalemia, hypertrophic obstructive cardiomyopathy, idiopathic hypertrophic subaortic stenosis, severe arterial hypertension, aneurysm of any location or other severe cardiovascular diseases (coronary artery disease, tachyarrhythmia or severe heart failure), QT interval prolongation (formoterol administration may cause QT_c interval prolongation).

Use in Pregnancy and Lactation

Pregnancy

Clinical studies on the use of Symbicort^® Rapihaler or budesonide in combination with formoterol during pregnancy have not been conducted.

In preclinical studies of embryofetal development with inhalation administration of Symbicort^® Rapihaler to rats, no additional effects due to the combined use of the active substances, or effects due to excipients were identified.

In preclinical studies, an adverse effect of budesonide on fetal development was identified. On the other hand, clinical observations of women during pregnancy did not reveal an increased risk of malformations with the use of budesonide. Reproductive function studies in animals have revealed adverse effects on the fetus at very high systemic exposures of formoterol. There are no adequate clinical data regarding the use of formoterol in pregnant women.

Accordingly, the use of Symbicort^® Rapihaler during pregnancy is possible only if the potential benefit to the mother outweighs the potential risk to the fetus. In particular, in the first trimester and shortly before childbirth, Symbicort^® Rapihaler should be used only if there are serious reasons for prescription.

Based on numerous available scientific data, the risk of adverse effects on the fetus with accidental use is minimal.

Breastfeeding period

A clinical pharmacology study showed that budesonide, when administered by inhalation, passes into breast milk. However, budesonide was not detected in the blood of the breastfed child. Based on pharmacokinetic parameters, it can be assumed that the concentration in the child’s plasma reaches less than 0.17% of the concentration in the mother’s plasma. Thus, no effect of budesonide on the child is expected when the mother takes Symbicort^® Rapihaler in therapeutic doses.

It is not known whether formoterol passes into breast milk. In female rats, formoterol was found in milk in small quantities. The use of Symbicort^® Rapihaler during breastfeeding is possible only if there are serious reasons for prescription.

Use in Hepatic Impairment

There are no data on the use of Symbicort^® Rapihaler in patients with impaired liver function.

The elimination of budesonide and formoterol occurs mainly through metabolism in the liver, so increased exposure is possible in patients with severe liver disease. Such patients should be closely monitored.

Use in Renal Impairment

There are no data on the use of Symbicort^® Rapihaler in patients with impaired renal function.

Pediatric Use

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

The drug with a dosage of 160 mcg + 4.5 mcg/dose is contraindicated in children under 12 years of age.

Geriatric Use

No dose adjustment is required for elderly patients.

Special Precautions

It is recommended to gradually reduce the dose of the drug before discontinuing treatment and it is not recommended to abruptly stop treatment.

Symbicort^® Rapihaler is not intended for initial therapy selection in bronchial asthma.

If therapy is insufficiently effective, a doctor’s consultation is necessary.

Unexpected and progressive worsening of COPD symptom control is a potentially life-threatening condition and requires urgent medical intervention. In this situation, the possibility of increasing the dose of corticosteroids, for example, prescribing a course of oral corticosteroids, or treatment with antibiotics in case of associated infection, should be considered.

A large American study evaluated the safety of salmeterol, another β₂-adrenoceptor agonist, compared with placebo in addition to usual therapy. An increase in the frequency of asthma-related deaths was shown in patients receiving salmeterol compared with patients receiving placebo (13/13176 [0.10%] vs. 3/13179 [0.02%]). However, to date, there are no results from studies assessing the frequency of asthma-related deaths in patients receiving formoterol, the active substance of Symbicort^® Rapihaler. It is possible that the increased risk of asthma-related death with salmeterol treatment is associated with a class-specific effect of β₂-adrenoceptor agonists, which include formoterol.

Patients are advised to always carry an inhaled medication for relief of attacks.

The patient’s attention should be drawn to the need for regular intake of the maintenance dose of Symbicort^® Rapihaler as prescribed by the doctor, even in the absence of disease symptoms.

If bronchial asthma symptoms are controlled, the dose of Symbicort^® Rapihaler can be gradually reduced, while it is important to constantly monitor the patients’ condition. The lowest effective dose of Symbicort^® Rapihaler should be prescribed.

Treatment with Symbicort^® Rapihaler should not be started during an exacerbation or significant worsening of bronchial asthma.

During therapy with Symbicort^® Rapihaler, exacerbations of bronchial asthma and serious adverse events associated with bronchial asthma may occur. Patients should continue treatment but seek medical help if asthma symptoms are not controlled or if their condition worsens after starting therapy.

Clinical study data for Symbicort^® in COPD patients with pre-bronchodilator FEV₁<50% predicted and post-bronchodilator FEV₁<70% predicted are lacking.

As with any other inhalation therapy, paradoxical bronchospasm may occur with immediate worsening of wheezing and shortness of breath after taking a dose of the drug. In such a case, therapy with Symbicort^® should be discontinued, treatment tactics should be reviewed and, if necessary, alternative therapy should be prescribed. In case of paradoxical bronchospasm, a rapid-acting inhaled bronchodilator should be used immediately.

Systemic effects may occur with the use of any inhaled corticosteroids, especially when using drugs in high doses for a long period of time. The manifestation of systemic effects is less likely with inhalation therapy than with the use of oral corticosteroids. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract and glaucoma.

It is recommended to regularly monitor the growth of children receiving long-term inhaled corticosteroids. If growth retardation is established, therapy should be reviewed to reduce the dose of the inhaled corticosteroid. The benefit-risk ratio of corticosteroid therapy and the possible risk of growth retardation should be carefully assessed. Based on limited data from long-term corticosteroid use studies, it can be assumed that most children and adolescents receiving inhaled budesonide therapy will ultimately achieve normal adult height. However, a small short-term growth retardation, mainly in the first year of treatment, has been reported.

Children taking immunosuppressants, including corticosteroids, are more susceptible to infectious diseases than healthy children. For example, chickenpox and measles can have a very severe course and sometimes be fatal. Special care must be taken and children and adults with weakened immune systems should not be exposed to the risk of virus infection. If there is a risk of chickenpox infection, treatment with immunoglobulins locally or a mixture of immunoglobulins intravenously is prescribed. If signs and symptoms of chickenpox are present, antiviral treatment should be prescribed. Anti-asthmatic therapy should be continued in case of viral upper respiratory tract infection. Those patients who have severe exacerbations of bronchial asthma against the background of viral respiratory tract infection should be prescribed short-term oral corticosteroid treatment.

Due to the potential effect of inhaled corticosteroids on bone mineral density, special attention should be paid to patients with risk factors for osteoporosis taking high doses of the drug for a long period. Studies of long-term use of inhaled budesonide in children at an average daily dose of 400 mcg (metered dose) or in adults at a daily dose of 800 mcg (metered dose) did not show a significant effect on bone mineral density. There are no data regarding the effect of higher doses of Symbicort^® on bone mineral density.

If there is reason to believe that adrenal function was impaired during prior systemic corticosteroid therapy, precautions should be taken when switching patients to treatment with Symbicort^®.

The benefits of inhaled therapy with budesonide generally minimize the need for oral corticosteroids; however, patients discontinuing oral corticosteroid therapy may have insufficient adrenal function for a long time. Patients who previously required emergency high-dose corticosteroids or received long-term treatment with high-dose inhaled corticosteroids may also belong to this risk group. The additional administration of corticosteroids should be provided for during periods of stress or surgery.

The patient should be instructed to rinse the mouth with water after inhalation to reduce the risk of oropharyngeal candidiasis. It is also necessary to rinse the mouth with water after inhalation in case of development of oropharyngeal candidiasis.

Precautions should be observed when treating patients with a prolonged QT_c interval. Administration of formoterol may cause prolongation of the QT_c interval.

The necessity and dose of inhaled corticosteroids should be reconsidered in patients with active or inactive forms of pulmonary tuberculosis, fungal, viral, or bacterial respiratory infections.

When beta₂-adrenergic agonists are co-administered with drugs that may cause or enhance a hypokalemic effect, such as xanthine derivatives, steroids, or diuretics, the hypokalemic effect of beta₂-adrenergic agonists may be enhanced. Special precautions should be observed in patients with unstable bronchial asthma using short-acting bronchodilators, as the risk of hypokalemia increases against the background of hypoxia. In such cases, it is recommended to monitor serum potassium levels.

The use of formoterol at a dose of 90 mcg for 3 hours by patients with acute bronchial obstruction was safe. Blood glucose levels should be monitored in patients with diabetes mellitus during treatment.

Clinical studies and meta-analyses have shown that the use of inhaled corticosteroids in COPD may lead to an increased risk of pneumonia. However, the absolute risk with budesonide is small. A meta-analysis of 11 double-blind studies involving 10,570 patients with COPD did not demonstrate a statistically significant increase in the risk of pneumonia in patients treated with budesonide (including in combination with formoterol) compared with patients receiving therapy without budesonide (placebo or formoterol). The incidence of the serious adverse event of pneumonia was 1.9% per year with therapy including budesonide and 1.5% per year with therapy without budesonide. The pooled risk ratio for therapy including budesonide compared to therapy without budesonide was 1.15 (95% confidence interval (CI): 0.83, 1.57). The pooled risk ratio for budesonide/formoterol compared to formoterol or placebo was 1.00 (95% CI: 0.69, 1.44). A causal relationship between the development of pneumonia and the use of drugs containing budesonide has not been established.

Effect on the Ability to Drive Vehicles and Operate Machinery

Symbicort^® Rapihaler is not expected to affect the ability to drive vehicles and operate machinery.

Overdose

Budesonide

Inhalation use in doses exceeding the recommended ones may lead to temporary or prolonged suppression of the hypothalamic-pituitary-adrenal system. In acute overdose of budesonide, even with excessive doses, clinically significant effects are not expected. With chronic use of the drug in excessive doses, systemic effects of corticosteroids may appear.

Formoterol

In case of formoterol overdose, effects typical for β₂-adrenoceptor agonists are likely to develop: tremor, headache, nausea, vomiting, palpitations, tachycardia, tachyarrhythmia, angina pectoris, as well as increase or decrease in blood pressure, nervousness, muscle cramps, dizziness, metabolic acidosis, hypokalemia, and hyperglycemia. In case of formoterol overdose, symptomatic supportive treatment is recommended.

Severe Overdose

If less than an hour has passed since a high oral dose of the drug was taken and severe intoxication cannot be ruled out, the following measures are recommended: gastric lavage and subsequent administration of activated charcoal (repeatedly if necessary), monitoring and correction of electrolyte balance and acid-base balance disorders, administration of cardioselective beta-blockers with caution due to the possible development of a bronchial asthma attack.

Drug Interactions

Administration of 200 mg ketoconazole once daily increased the plasma concentration of budesonide (a single oral dose of 3 mg) when used concomitantly, on average, by 6 times. When ketoconazole was administered 12 hours after budesonide intake, the plasma concentration of the latter increased, on average, by 3 times. Information on such interaction with high-dose inhaled budesonide is not available, but a significant increase in the plasma concentration of the drug is possible. There are no recommendations for dose adjustment; the above combination of drugs should be avoided. If this is not possible, the time interval between the administration of a cytochrome CYP3A4 isoenzyme inhibitor and budesonide should be maximized. The possibility of reducing the budesonide dose should also be considered. Other potent CYP3A4 inhibitors are also likely to significantly increase the plasma concentration of budesonide. Maintenance therapy with Symbicort^® Rapihaler is not recommended for patients receiving potent CYP3A4 inhibitors.

Beta-adrenergic receptor blockers may weaken or inhibit the effect of formoterol. Symbicort^® Rapihaler should not be prescribed concomitantly with beta-blockers (including eye drops), except in compelling cases.

Concomitant use of Symbicort^® Rapihaler with quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), MAO inhibitors, and tricyclic antidepressants may prolong the QT_c interval and increase the risk of ventricular arrhythmias.

In addition, levodopa, levothyroxine, oxytocin, and ethanol may reduce the tolerance of the heart muscle to beta₂-adrenergic agonists.

Concomitant use of MAO inhibitors, as well as drugs with similar properties, such as furazolidone and procarbazine, may cause an increase in blood pressure.

There is an increased risk of arrhythmias in patients undergoing general anesthesia with halogenated hydrocarbon agents while using Symbicort^® Rapihaler.

When Symbicort^® Rapihaler is used concomitantly with other beta-adrenergic agonists or with anticholinergic drugs, the side effects of formoterol may be enhanced.

Hypokalemia may occur as a result of the use of beta₂-adrenergic agonists, which may be enhanced by concomitant treatment with xanthine derivatives, mineralocorticosteroids, or diuretics. Hypokalemia may increase the risk of cardiac arrhythmias in patients taking cardiac glycosides.

No interaction of budesonide and formoterol with other drugs used to treat bronchial asthma has been noted.

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; after first opening the pouch – 3 months. Do not use after the expiration date stated on the packaging.

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.