Symbicort Turbuhaler, 160+4, 5 mcg/dose 120 doses

Pharmacotherapeutic group: bronchodilator combined (beta2-adrenomimetic selective + local glucocorticosteroid)

ATX code: R03AK07

Pharmacological properties

Pharmacodynamics

Simbicort® contains budesonide and formoterol, which have different mechanisms of action and have an additive effect in reducing the frequency of exacerbations of bronchial asthma. The special properties of budesonide and formoterol make it possible to use their combination to relieve attacks/symptoms with an anti-inflammatory effect, or as maintenance therapy for bronchial asthma.

Budesonide. Budesonide is a glucocorticosteroid that has a rapid (within hours) and dose-dependent anti-inflammatory effect on the airways after inhalation, reducing the severity of symptoms and the frequency of exacerbations of bronchial asthma. When prescribing inhaled budesonide, there is a lower incidence of serious adverse effects than when using systemic glucocorticosteroids. It reduces the severity of bronchial mucosal edema, mucus production, sputum formation and airway hyperresponsiveness. The exact mechanism of anti-inflammatory action of glucocorticosteroids is unknown.

Formoterol. Formoterol is a selective b2-adrenoreceptor agonist, after inhalation of which there is rapid and prolonged relaxation of bronchial smooth muscle in patients with reversible airway obstruction. The dose-dependent bronchodilator effect occurs within 1-3 minutes after inhalation and persists for at least 12 hours after a single dose.

Simbicort® Turbukhaler®: Budesonide + Formoterol Bronchial asthma

Clinical effectiveness of Simbicort® as an anti-inflammatory attack/symptom therapy: For anti-inflammatory seizure/symptom control (therapy A) and as maintenance therapy and for anti-inflammatory seizure/symptom control (therapy B)

. A total of 7 double-blind clinical trials enrolled 20140 patients with bronchial asthma, 7831 of whom were randomized to therapy with Symbicort® for attack/symptom control with anti-inflammatory effects and with or without maintenance therapy (therapy B) (therapy A).

In two studies (SYGMA 1 and SYGMA 2) involving 8064 patients with mild bronchial asthma, 3384 patients received Symbicort® for attack/symptom control with anti-inflammatory action (therapy A) for 12 months.

In the SYGMA 2 study, Symbicort® 160/4.5 mcg when used on-demand in response to symptoms (for attack/symptom management with anti-inflammatory action – therapy A) was comparable to maintenance dose budesonide (1 inhaled 200 mcg/dose twice daily) combined with a short-acting beta2-adrenomimetic on demand with respect to the frequency of severe exacerbations. Prevention of severe exacerbations was achieved with a 75% reduction in median steroid load and without the need for adherence to maintenance therapy with inhaled glucocorticosteroids. In the SYGMA 1 trial, Symbicort® for anti-inflammatory attack/symptoms provided a statistically significant and clinically meaningful 64% reduction in the annual incidence of severe exacerbations compared to on-demand use of a short-acting beta2-adrenomimetic. The reduction in the annual incidence of moderate to severe exacerbations was 60%.

. In the SYGMA 1 study, Symbicort® 160/4.5 mcg on-demand was superior to short-acting beta2-adrenomimetic on-demand with respect to bronchial asthma symptom control, showing an average of 34.4% and 31.1% of weeks with good bronchial asthma control, respectively, but was less effective compared with maintenance dose budesonide (1 inhaled 200 mcg/dose twice daily) in combination with an on-demand short-acting beta2-adrenomimetic, with a mean of 34.4% and 44.4% weeks with good bronchial asthma control, respectively. Symbicort® for anti-inflammatory attack/symptoms was superior to the on-demand short-acting beta2-adrenomimetic in terms of improved bronchial asthma control (based on results from the Asthma Control Assessment Questionnaire of 5 items (ACQ5)). Improvement in disease control was less pronounced with Symbicort® on-demand compared to maintenance dose budesonide (1 inhaled 200 mcg/dose twice daily) in combination with a short-acting beta2-adrenomimetic on-demand. The mean difference in the effect of ACQ5 therapy was not clinically significant in either comparison (assessed by a difference of 0.5 or more). These results were observed in a clinical trial setting with significantly higher adherence to budesonide maintenance therapy than in actual practice.

In the SYGMA trials, improvement in pulmonary function relative to baseline (mean prebronchodilator BEP1) was statistically significantly greater in patients receiving Symbicort® for anti-inflammatory seizure/symptoms compared with patients receiving an on-demand beta2-adrenomimetic short-acting. Statistically significantly less improvement in lung function was noted with Symbicort® on-demand compared with budesonide maintenance dose (1 inhaled 200 mcg/dose twice daily) in combination with a short-acting beta2-adrenomimetic on-demand. For both comparisons, the mean differences in therapy effect were small (approximately 30 to 55 mL, corresponding to approximately 2% of the baseline mean).

. In another clinical program involving 12076 patients in 5 studies, an observational study of 4447 patients treated with Symbicort® as maintenance therapy and for seizure/symptom control with anti-inflammatory action (therapy B) for 6 to 12 months There was a statistically and clinically significant reduction in the number of severe exacerbations and increased time to first exacerbation compared to a combination of Symbicort® or budesonide as maintenance therapy and a beta2-adrenoceptor for seizure control. There was also effective control of disease symptoms, pulmonary function, and a reduction in the frequency of prescription of inhalation for seizure control. No development of tolerance to prescribed therapy was detected.

The results of 6 double-blind studies with 14385 patients with bronchial asthma (including 1847 adolescents) demonstrated comparable efficacy and safety of the drug in adolescent and adult patients. The number of adolescent patients taking more than 8 inhalations for at least one day as maintenance therapy and to control attacks/symptoms with anti-inflammatory effects was limited, and use in this regimen was infrequent.

In patients who sought care for an acute asthma attack, Symptom Control (relief of bronchospasm) was as rapid and effective after inhalation of Symbicort® as after prescription of salbutamol and formoterol.

Clinical effectiveness of Simbicort® as maintenance therapy (therapy C)

The addition of formoterol to budesonide reduces asthma symptoms, improves lung function and reduces the rate of exacerbations.

The effect of Simbicort® Turbukhaler® on lung function is consistent with the effect of the combination of budesonide and formoterol monotherapies and greater than that of budesonide alone. In all cases, a short-acting beta2-adrenoceptor was used for seizure control. No decrease of antiasthmatic effect with time was noted. The drug has good tolerability.

Symbicort® Turbukhaler® as maintenance therapy in combination with short-acting beta2-adrenoceptor for seizure control was administered to patients aged 6 to 11 years for 12 weeks (two inhalations of 80/4.5 mcg/dose twice daily). Improvements in pulmonary function and good tolerability of therapy compared to the corresponding dose of budesonide Turbukhaler® were noted.

Chronic Obstructive Pulmonary Disease (COPD)

In two studies lasting 12 months in patients with moderate to severe COPD (baseline: prebronchodilatation SPH1 < 50% of proper; median postbronchodilatation SPH1 = 42% of proper), there was a significant reduction in the rate of exacerbations of the disease when taking Symbicort® Turbuhaler® compared with patients who received formoterol or placebo alone as therapy (mean exacerbation rate 1.4 compared with 1.8-1.9 in the placebo/formoterol group). No difference was noted between Symbicort® and formoterol administration on first-second forced expiratory volume (FEF1).

Pharmacokinetics Intake

Symbicort® Turbuhaler® is bioequivalent to the corresponding monotherapies with respect to the systemic effects of budesonide and formoterol. Despite this, a slight increase in cortisol suppression was noted after administration of Symbicort® Turbuhaler® compared to monotherapies. This difference has no effect on clinical safety. There is no evidence of pharmacokinetic interaction between budesonide and formoterol.

The pharmacokinetic parameters for the respective substances are comparable after administration of budesonide and formoterol as monotherapy and as part of Symbicort® Turbukhaler®. For budesonide, when administered as part of the combination drug, the area under the concentration-time curve (AUC) is slightly greater, the drug is absorbed faster and the value of maximum plasma concentration is higher.

For formoterol when given as part of a combination drug, the maximum plasma concentration is the same as for the mono drug.

Inhaled budesonide is rapidly absorbed and reaches maximum plasma concentration 30 minutes after inhalation. The average dose of budesonide delivered to the lungs after inhalation via Turbulhaler® is 32-44% of the delivered dose. Systemic bioavailability is approximately 49% of the delivered dose. In children aged 6 to 16 years, the average dose of budesonide delivered to the lungs after inhalation via Turbulhaler® does not differ from that in adult patients (the final plasma concentration of the drug was not determined).

Inhaled formoterol is rapidly absorbed and reaches maximum plasma concentration 10 minutes after inhalation. The average dose of formoterol delivered to the lungs after inhalation via Turbuhaler® is 28-49% of the delivered dose. Systemic bioavailability is about 61% of the delivered dose.

Distribution and metabolism

Approximately 50% of formoterol and 90% of budesonide bind to plasma proteins. The volume of distribution for formoterol is about 4 l/kg and for budesonide about 3 l/kg. Formoterol is inactivated by conjugation (active O-demethylated metabolites are formed mainly as inactivated conjugates). Budesonide undergoes intensive biotransformation (about 90%) during the first passage through the liver to form metabolites with low glucocorticosteroid activity. Glucocorticosteroid activity of the main metabolites – 6-b-hydroxybudesonide and 16-a-hydroxyprednisolone – does not exceed 1% of similar activity of budesonide. There is no evidence of metabolite interaction or substitution reaction between budesonide and formoterol.

The bulk of the formoterol dose is metabolized in the liver and then excreted by the kidneys: after inhalation, 8-13% of the delivered dose of formoterol is excreted unchanged. Formoterol has a high systemic clearance (approximately 1.4 L/min); the half-life of the drug is on average 17 hours.

Budesonide is metabolized mainly with participation of CYP3A4 isoenzyme. Budesonide metabolites are excreted by the kidneys unchanged or in the form of conjugates.

Only small amounts of unchanged budesonide are detected in the urine. Budesonide has a high systemic clearance (approximately 1.2 L/min).

The pharmacokinetics of formoterol and budesonide in patients with renal impairment have not been studied. Plasma concentrations of budesonide and formoterol may be increased in patients with liver disease.

Indications

Active ingredient

Composition

How to take, the dosage

For inhaled use.

80/4.5 µg/dose

Symbicort® is not indicated for the initial treatment of bronchial asthma.

The dosage of Symbicort® is adjusted individually and according to the severity of the disease. This must be taken into account not only when starting treatment with the combination drugs, but also when changing the maintenance dose of the drug.

Patients must have ongoing monitoring by their physician to ensure that the dose of Symbicort® Turbukhaler® is appropriately adjusted.

Symbicort® Turbuhaler® can be used according to different approaches to therapy:

B. Symbicort® Turbuhaler® as maintenance therapy and for relief of attacks/symptoms with anti-inflammatory effects.

C. Symbicort® Turbuhaler® as maintenance therapy (fixed

dose).

If maintenance therapy with a combination of an inhaled glucocorticosteroid and a long-acting beta2-adrenoceptor agonist is necessary, the patient may take Simbicort® Turbuhaler® as maintenance therapy and in addition for seizure/symptom management with anti-inflammatory effects. The patient should have Symbicort® on hand at all times for symptom relief. Symbicort® as maintenance therapy and for relief of attacks/symptoms with anti-inflammatory effects is particularly indicated for patients with:

Adults and adolescents (12 years and older): The recommended dose for maintenance therapy is 2 inhalations per day, taken 1 inhalation in the morning and evening, or 2 inhalations once in the morning or evening only. If symptoms occur, 1 additional inhalation is taken. If symptoms continue to increase within a few minutes, 1 additional inhalation is prescribed, but no more than 6 inhalations to end 1 attack.

It is not usually necessary to prescribe more than 8 inhalations per day, but the number of inhalations may be increased to 12 per day for short periods of time. Patients receiving more than 8 inhalations per day are advised to seek medical advice to revise therapy.

Dose-dependent side effects in patients using large numbers of inhalations to control seizures require close monitoring.

Children younger than 12 years: Simbicort® Turbukhaler® is not recommended for maintenance therapy and for relief of attacks/symptoms with anti-inflammatory effects in children younger than 12 years.

If maintenance therapy with a combination of an inhaled glucocorticosteroid and a long-acting beta2-adrenoreceptor agonist is needed, the patient may take Symbicort® Turbuhaler® in a fixed daily dose and use a separate short-acting bronchodilator for symptom relief. Adults (18 years and older): 1 to 2 inhalations twice daily. If necessary, it is possible to increase the dose to 4 inhalations twice a day.

Adolescents (12-17 years old): 1 to 2 inhalations twice a day.

Children 6-11 years old: 1 to 2 inhalations twice a day.

Children under 6 years of age: Simbicort® Turbukhaler® is not recommended for children under 6 years of age.

The dose should be reduced to the lowest dose against which optimal control of bronchial asthma symptoms is maintained. After optimal control of bronchial asthma symptoms is achieved with twice-daily dosing, it is recommended that the dose be titrated to the lowest effective dose, up to once-daily dosing, when the physician believes the patient requires maintenance therapy with a long-acting bronchodilator in combination with an inhaled glucocorticosteroid.

When individual patients require a different active ingredient dose combination than in Symbicort® Turbuhaler®, beta2-adrenomimetics and/or glucocorticosteroids in separate inhalers should be prescribed.

The increased frequency of use of short-acting beta2-adrenomimetics is an indication that overall disease control is worsening and requires a review of anti-asthmatic therapy.

Special patient groups: There is no need for special selection of the drug dose for elderly patients. There are no data on the use of Simbicort® in patients with renal or hepatic impairment. Because budesonide and formoterol are primarily eliminated by hepatic metabolism, a slower elimination rate can be expected in patients with severe hepatic cirrhosis.

160/4.5 mcg/dose

. The dosage of Symbicort® is adjusted individually and according to the severity of the disease. This must be taken into account not only when starting treatment with the combination drugs, but also when changing the maintenance dose of the drug.

Patients must have ongoing monitoring by their physician to ensure that the dose of Symbicort® Turbukhaler® is appropriately adjusted.

Symbicort® Turbuhaler® can be used according to different approaches to therapy:

A. Symbicort® Turbuhaler® for relief of attacks/symptoms with anti-inflammatory effects (patients with mild bronchial asthma).

B. Symbicort® Turbukhaler® as maintenance therapy and for relieving attacks/symptoms with anti-inflammatory action.

Alternatively, Symbicort® Turbuhaler® may be used as fixed-dose therapy:

C. Symbicort® Turbuhaler® as maintenance therapy (fixed dose).

Simbicort® Turbukhaler® is taken on demand to relieve bronchial asthma symptoms when they develop and to prevent bronchoconstriction caused by allergens or exercise (or to prevent symptoms in situations assessed by the patient as likely to provoke an asthma attack). Formoterol, the active ingredient in Simbicort® Turbukhaler®, provides a rapid onset of action (within 1-3 minutes) with prolonged bronchodilation (at least 12 hours after a single dose) for reversible airway obstruction. The patient should have Symbicort® Turbukhaler® on hand at all times for symptomatic relief.

The physician should discuss allergen exposure and exercise volume with the patient and consider them when recommending the frequency of administration.

Adults and adolescents (12 years and older): Patients should take 1 inhalation on demand when symptoms develop and to prevent bronchoconstriction caused by allergens or exercise to control bronchial asthma. If symptoms further escalate within a few minutes, 1 additional inhalation is prescribed, but no more than 6 inhalations to control 1 attack.

No more than 8 inhalations per day are usually required, but the number of inhalations may be increased to 12 per day for short periods of time. Patients receiving more than 8 inhalations per day are advised to seek medical attention for reassessment and review of bronchial asthma therapy.

Dose-dependent side effects in patients using large numbers of inhalations on demand require close monitoring.

Children younger than 12 years: The efficacy and safety of Symbicort® Turbuhaler® for relief of attacks/symptoms with anti-inflammatory effects in children younger than 12 years have not been studied.

If maintenance therapy with a combination of an inhaled glucocorticosteroid and a long-term beta2-adrenoreceptor agonist is necessary, the patient may take Simbicort® Turbuhaler® as maintenance therapy and in addition for relief of attacks/symptoms with anti-inflammatory effects. The patient should have Symbicort® on hand at all times for symptom relief. Symbicort® as maintenance therapy and for relief of attacks/symptoms with anti-inflammatory effects is particularly indicated for patients with:

The physician should discuss allergen exposure and exercise volume with the patient and consider these in recommending the frequency of therapy.

Adults and adolescents (12 years and older): Patients should take 1 inhalation on demand when symptoms develop and to prevent bronchoconstriction caused by allergens or exercise to control bronchial asthma. If symptoms further increase within a few minutes, 1 additional inhalation is prescribed, but no more than 6 inhalations to control 1 attack. Patients also take the recommended maintenance dose of 2 inhalations per day, 1 inhalation in the morning and evening or 2 inhalations once in the morning or evening only. For some patients, a maintenance dose of 2 inhalations twice a day may be prescribed.

It is not usually necessary to prescribe more than 8 inhalations per day, but the number of inhalations may be increased to 12 per day for short periods of time. Patients receiving more than 8 inhalations per day are advised to seek medical advice to reassess and review maintenance therapy.

Dose-dependent side effects in patients using large numbers of inhalations on demand require close monitoring.

Children under 12 years of age: Simbicort® Turbukhaler® as maintenance therapy and for relief of attacks/symptoms with anti-inflammatory effects is not recommended for children under 12 years of age.

If maintenance therapy with a combination of an inhaled glucocorticosteroid and a long-acting beta2-adrenoreceptor agonist is needed, the patient may take Symbicort® Turbuhaler® in a fixed daily dose and use a separate short-acting bronchodilator for symptom relief. Adults (18 years and older): 1 to 2 inhalations twice daily. If necessary, it is possible to increase the dose to 4 inhalations twice a day.

Adolescents (12-17 years old): 1 to 2 inhalations twice a day.

Children aged 6-11 years: For children aged 6-11 years, a lower dosage (80/4.5 mcg/dose) is available.

Children under 6 years of age: Simbicort® Turbukhaler® is not recommended for children under 6 years of age.

The dose should be reduced to the lowest dose against which optimal control of bronchial asthma symptoms is maintained. After optimal control of bronchial asthma symptoms is achieved with twice-daily dosing, it is recommended that the dose be titrated to the lowest effective dose, up to once-daily dosing, when the physician believes the patient requires maintenance therapy with a long-acting bronchodilator in combination with an inhaled glucocorticosteroid.

When individual patients require a different active ingredient dose combination than in Symbicort® Turbuhaler®, beta2-adrenomimetics and/or glucocorticosteroids in separate inhalers should be prescribed.

The increased frequency of use of short-acting beta2-adrenomimetics is an indicator of worsening overall disease control and requires a review of anti-asthmatic therapy.

Adults: 2 inhalations twice daily.

Special patient groups: There is no need for special selection of the dose of the drug for elderly patients. There are no data on the use of Simbicort® in patients with renal or hepatic impairment. Because budesonide and formoterol are primarily eliminated by hepatic metabolism, a slower excretion rate can be expected in patients with severe hepatic cirrhosis.

Interaction

Special Instructions

Synopsis

Contraindications

Side effects

There has been no increase in the incidence of adverse reactions when using budesonide and formoterol together. The most common adverse reactions associated with the use of the drug are such pharmacologically expected for

b2-adrenomimetics adverse events such as tremor and palpitations; symptoms are usually of moderate severity and resolve on their own after a few days of treatment.

The adverse reactions associated with the use of budesonide or formoterol are listed below by organ system class and frequency of occurrence. The frequency of reactions is graded as follows: very common (≥1/10), common (≥1/100, < 1/10), infrequent (≥1/1000, < 1/100), rare (≥1/10000, < 1/1000), very rare (< 1/10000).

Infections and invasions: often – candidiasis of mucous membranes of the oral cavity and pharynx, pneumonia (in patients with COPD)

Immune system disorders: rare – immediate and delayed-type hypersensitivity reactions (e.g., dermatitis, exanthema, urticaria, skin itching, angioedema, anaphylactic reaction)

Metabolic and nutritional disorders: rare – hypokalemia; very rare – hyperglycemia, signs or symptoms of systemic effects of glucocorticosteroids (including adrenal hypofunction)

Mental disorders: infrequent – psychomotor agitation, anxiety, sleep disorders; very rare – depression, behavior disorders (mainly in children)

Nervous system disorders: frequent – headache, tremor; infrequent – dizziness; very rare – taste disorders

Heart and vascular disorders: frequent – palpitations; infrequent – tachycardia; rare – arrhythmia (e.g., atrial fibrillation, supraventricular tachycardia, extrasystole); very rare – angina pectoris, blood pressure fluctuations

Respiratory system, chest and mediastinum disorders: common – cough, hoarseness of voice, mild irritation of the pharyngeal mucosa; rarely – bronchospasm

Gastrointestinal disorders: infrequent – nausea

Skin and subcutaneous tissue disorders: infrequent – bruising

Musculoskeletal and connective tissue disorders: infrequent – muscle cramps

Systemic effects of inhaled glucocorticosteroids may occur when using high doses for a long time.

The use of b2-adrenomimetics may increase blood levels of insulin, free fatty acids, glycerol and ketone bodies.

Overdose

Pregnancy use

Similarities