Efficacy and safety of Symbicort 80/4.5 mcg, used in a flexible dosing regimen in children aged 6 to 12 years suffering from bronchial asthma

Symbicort turbuhaler

Symbicort® Turbuhaler® is not intended for the initial treatment of intermittent and mild persistent bronchial asthma.

The dose selection of the drugs included in Symbicort Turbuhaler is carried out individually and depending on the severity of the disease. This must be taken into account not only when starting treatment with combination drugs, but also when changing the dose of the drug.

If individual patients require a different combination of doses of active substances than in Symbicort® Turbuhaler®, beta2-adrenergic agonists and/or corticosteroids should be prescribed separately in separate inhalers.

Bronchial asthma

Symbicort® Turbuhaler® 80/4.5 mcg/dose and 160/4.5 mcg/dose

Patients should be under constant medical supervision to ensure adequate dosage adjustment of Symbicort Turbuhaler. The dose should be reduced to the lowest dose that maintains optimal control of asthma symptoms. Once complete control over the symptoms of bronchial asthma is achieved against the background of the minimum recommended dose of the drug, at the next stage you can try prescribing monotherapy with inhaled corticosteroids.

There are two approaches to prescribing therapy with Symbicort Turbuhaler:

• as maintenance therapy, Symbicort® Turbuhaler® is prescribed for continuous maintenance therapy in combination with a separate short-acting beta2-adrenergic agonist to relieve attacks;
• as maintenance therapy and for the relief of attacks, Symbicort® Turbuhaler® is prescribed both for continuous maintenance therapy and on demand when symptoms appear.

As maintenance therapy

The patient must always have with him a separate inhaler with a short-acting beta2-adrenergic agonist to relieve attacks.

Adults (18 years and older) are prescribed Symbicort® Turbuhaler® 80/4.5 mcg/dose and 160/4.5 mcg/dose, 1-2 inhalations 2 times a day. If necessary, the dose can be increased to 4 inhalations 2 times a day.

Adolescents (12-17 years old) are prescribed Symbicort® Turbuhaler® 80/4.5 mcg/dose and 160/4.5 mcg/dose, 1-2 inhalations 2 times a day.

Children over 6 years of age are prescribed Symbicort® Turbuhaler® 80/4.5 mcg/dose, 1-2 inhalations 2 times a day.

After achieving optimal control of symptoms of bronchial asthma while taking the drug 2 times a day, it is recommended to titrate the dose to the lowest effective dose, up to 1 time a day, in cases where, in the opinion of the doctor, the patient requires maintenance therapy in combination with long-acting bronchodilators.

An increase in the frequency of use of short-acting beta2-agonists is an indicator of deterioration in overall disease control and requires a review of anti-asthma therapy.

As maintenance therapy and to relieve attacks

The patient must always have Symbicort® Turbuhaler® with him to relieve attacks.

In this case, the drug is especially indicated for patients with insufficient control of bronchial asthma and the need for frequent use of drugs to relieve attacks; if there is a history of exacerbations of bronchial asthma that required medical intervention.

It is necessary to carefully monitor the occurrence of dose-dependent side effects in patients using a large number of inhalations to relieve attacks.

Adults (18 years and older) are prescribed Symbicort® Turbuhaler® 80/4.5 mcg/dose and 160/4.5 mcg/dose; The recommended dose is 2 inhalations per day: 1 inhalation in the morning and evening, or 2 inhalations 1 time per day only in the morning or only in the evening. Some patients may be prescribed a maintenance dose of Symbicort® Turbuhaler® 160/4.5 mcg/dose 2 inhalations 2 times a day. If symptoms occur, 1 additional inhalation is necessary. With a further increase in symptoms within a few minutes, 1 additional inhalation is prescribed, but no more than 6 inhalations to relieve 1 attack.

Usually it is not necessary to prescribe more than 8 inhalations per day, but you can increase the number of inhalations to 12 per day for a short time. In patients who use more than 8 inhalations per day, a review of therapy is recommended.

Symbicort® Turbuhaler® 80/4.5 mcg/dose and 160/4.5 mcg/dose as maintenance therapy and for the relief of attacks is not recommended for children and adolescents under the age of 18 years.

Symbicort® Turbuhaler® 320/9 mcg/dose

For adults (18 years and older), the drug is prescribed 1 inhalation 2 times a day. If necessary, the dose can be increased to 2 inhalations 2 times a day. After achieving optimal control of bronchial asthma symptoms while taking the drug 2 times a day, it is recommended to titrate the dose to the lowest effective dose, up to 1 time a day.

Adolescents aged 12-17 years are prescribed 1 inhalation 2 times a day.

Symbicort® Turbuhaler® 320/9 mcg/dose is not recommended for children under 12 years of age due to the lack of clinical data.

Patients should visit their doctor regularly to monitor the optimal dose of the drug. The dose should be reduced to the lowest dose that maintains optimal control of asthma symptoms. After achieving optimal control of symptoms of bronchial asthma while taking the drug 2 times a day, it is recommended to titrate the dose to the lowest effective dose, up to 1 time a day, in cases where, in the opinion of the doctor, the patient requires maintenance therapy in combination with long-acting bronchodilators.

COPD

Adults are prescribed Symbicort® Turbuhaler® 160/4.5 mcg/dose, 2 inhalations 2 times/day or Symbicort® Turbuhaler® 320/9 mcg/dose, 1 inhalation 2 times/day.

There is no need for special selection of the drug dose for elderly patients.

There is no data on the use of Symbicort Turbuhaler in patients with renal or hepatic impairment. Because As budesonide and formoterol are eliminated primarily through hepatic metabolism, a slower rate of elimination of the drug can be expected in patients with severe cirrhosis.

Rules for using the turbohaler

The mechanism of action of the turbuhaler is such that when the patient inhales through the mouthpiece, air currents carry the drug into the respiratory tract.

The patient must be instructed:

• carefully study the “Instructions for Use” of the turbuhaler;
• inhale forcefully and deeply through the mouthpiece to ensure that the optimal dose of the drug reaches the lungs;
• never exhale through the mouthpiece;
• in order to minimize the possibility of developing fungal infections of the oropharynx, rinse your mouth with water after each inhalation. It is also necessary to rinse your mouth with water after inhalation to relieve symptoms and in case of development of candidiasis of the oral mucosa and pharynx.

The patient may not taste or feel the drug after using Turbuhaler, due to the small amount of the substance delivered.

Instructions for use of turbuhaler

Turbuhaler is a multi-dose inhaler that allows you to dose and inhale the drug in very small doses. When inhaled, the powder from the turbuhaler is delivered to the lungs, so it is important that the patient inhales forcefully and deeply through the mouthpiece.

Before using the turbohaler for the first time, you must prepare it for use:

1. Unscrew and remove the cap.

2. Hold the inhaler vertically with the red dispenser facing down. Do not hold the inhaler by the mouthpiece while turning the dispenser. Turn the dispenser all the way in one direction, and then also all the way in the opposite direction. Perform the described procedure twice.

Now the inhaler is ready for use; it is not necessary to repeat this procedure for preparing the turbuhaler for use before each use.

To take one dose, the patient must complete the following procedure:

1. Unscrew and remove the cap.

2. Hold the inhaler vertically with the red dispenser facing down. Do not hold the inhaler by the mouthpiece while turning the dispenser. In order to measure the dose, turn the dispenser all the way in one direction, and then also all the way in the opposite direction. A clicking sound will be heard during this procedure.

3. Exhale. Do not exhale through the mouthpiece.

4. Gently place the mouthpiece between your teeth, purse your lips and inhale forcefully and deeply through your mouth. Do not chew or squeeze the mouthpiece with your teeth.

5. Before exhaling, remove the inhaler from your mouth.

6. If inhalation of more than one dose is required, paragraphs should be repeated. 2-5.

7. Close the inhaler with the cap and check that the inhaler cap is screwed on tightly.

8. Rinse your mouth with water without swallowing.

You cannot remove the mouthpiece, because it is attached to the inhaler and cannot be removed. The turbhaler mouthpiece rotates, but should not be turned unless necessary.

Because the amount of powder inhaled is very small, you may not be able to taste the powder after inhalation.

However, absolutely strict adherence to the instructions ensures inhalation (inhalation) of the required dose of the drug.

If the procedure for loading the inhaler was mistakenly repeated more than once before taking the drug, patients will still receive one dose of the drug when inhaled. In this case, the dose indicator will show the total number of measured doses.

The sound heard when the inhaler is shaken is produced by the drying agent, not the drug substance.

The need to replace the inhaler

The dose indicator shows the approximate number of doses remaining in the inhaler; dose counting upon filling the turbohaler begins with the 60th or 120th dose (depending on the total number of doses of the purchased turbohaler). The indicator shows an interval of 10 doses, so it does not show every dispensed (loaded) dose.

Turbuhaler delivers the required dose of the drug, even if no changes are noticeable in the dose indicator window.

The appearance of a red background in the dose indicator window means that there are 10 doses of the drug left in the turbuhaler. When the number 0 appears on a red background in the middle of the dose window, the inhaler should be thrown away.

Please note that even when the indicator window shows the number 0, the dispenser continues to rotate. However, the dose indicator stops recording the number of doses (stops moving) and the number 0 remains in the dose window of the inhaler.

Cleaning

Regularly (once a week) you should clean the outside of the mouthpiece with a dry cloth. Do not use water or other liquids to clean the mouthpiece.

Disposal

You should be careful when handling a used inhaler and be aware that some medication may remain inside the inhaler.

Overdose

Symptoms: In case of acute overdose of budesonide, even in significant doses, no clinically significant symptoms are expected. With chronic use of budesonide in excessive doses, systemic effects of GCS, such as hypercortisolism and suppression of adrenal function, may occur.

In case of formoterol overdose - tremor, headache, rapid heartbeat; in some cases, the development of tachycardia, hyperglycemia, hypokalemia, prolongation of the QTc interval, arrhythmia, nausea, and vomiting was reported.

In acute bronchial obstruction, taking formoterol at a dose of 90 mcg for 3 hours was safe.

Treatment: supportive and symptomatic treatment is indicated.

If it is necessary to discontinue Symbicort Turbuhaler due to an overdose of formoterol, which is part of the combination drug, the issue of prescribing an appropriate GCS should be considered.

Symbicort in the treatment of patients with stable COPD

Advances in the study and treatment of chronic obstructive pulmonary disease (COPD) in recent years have made it possible to consider it as a disease that can be prevented and treated [1]. The paradox of COPD is that no effective anti-inflammatory therapy has yet been found for this disease, which is based on chronic inflammation, which leads to structural changes in the proximal and distal parts of the bronchi, parenchyma and blood vessels of the lungs. Inflammation in COPD has its own characteristics that distinguish it from other diseases. Eosinophils, mast cells and CD4+ lymphocytes play a central role in the pathogenesis of bronchial asthma (BA). COPD, unlike asthma, is characterized by an inflammatory reaction involving neutrophils, macrophages and CD8+ lymphocytes. Differences in the mechanisms of inflammation in COPD and asthma underlie significant differences in pathological changes, symptoms and treatment approaches. BA is characterized by transient bronchoconstriction, and the inflammatory process responds well to corticosteroid therapy, both topical and systemic. In the case of COPD, there is a progressive, slightly reversible narrowing of the bronchi and the formation of emphysema [2]. Nonsteroidal anti-inflammatory drugs and antileukotriene drugs are not effective for COPD. Antibiotics and systemic corticosteroids are appropriate for exacerbations, but not for the treatment of stable COPD. Inhaled glucocorticosteroids in COPD If in BA, starting from the 2nd stage of disease severity (i.e. in most patients), the feasibility of long-term regular use of inhaled glucocorticosteroids (ICS) as a basic therapy has been proven, then in COPD the indications for ICS therapy given in the last the 2006 editions of the GOLD guideline, based on evidence-based medicine, apply only to patients with stage III (severe) disease that occurs with frequent (more than 1 per year) exacerbations. In this category of patients, the addition of ICS to therapy reduces the frequency of exacerbations and improves health status. It is assumed that long-term ICS therapy helps reduce mortality from all causes among patients with COPD, but additional prospective studies are required to clarify this situation. The safety of long-term ICS therapy also requires further study [1]. A recent meta-analysis of 47 primary studies, including a total of 13,139 patients, confirmed the above statements of GOLD. ICS therapy lasting from 2 to 6 months in patients with COPD led to a slight increase in FEV1. Long-term (more than 6 months) ICS therapy compared with placebo did not slow down the rate of decline in FEV1 and did not lead to a decrease in mortality among patients, but it did reduce the frequency of exacerbations of COPD and the rate of deterioration in the quality of life index according to the St. George's respiratory questionnaire. The effect of ICS therapy could not be predicted based on the outcome of treatment with systemic corticosteroids, response to bronchodilators, and the presence of bronchial hyperresponsiveness. Long-term ICS therapy created an increased risk of developing oropharyngeal candidiasis and hoarseness. Over 3 years of follow-up, there were no adverse effects on skeletal bone mineral density or the incidence of bone fractures [3]. Another general publication talks about the possibility of developing a wider range of undesirable effects as a result of long-term ICS therapy: hoarseness of voice, irritation of the pharyngeal mucosa, paradoxical bronchospasm, oropharyngeal candidiasis, allergic reactions, suppression of adrenal function, osteoporosis, growth retardation in children, cataracts, glaucoma , steroid myopathy and increased risk of pneumonia [4]. Thus, ICS monotherapy in patients with COPD, unlike BA, can be considered inappropriate, and the inclusion of ICS in treatment programs requires maintaining a balance between proven benefits and possible side effects, as well as the cost of treatment. Inhalation therapy of patients with COPD with a combination of bronchodilators and ICS. The features of the inflammatory process in COPD and the lack of drugs that can effectively influence it have led to the fact that today the basis of treatment for patients with COPD are bronchodilators - β2-agonists, anticholinergics and methylxanthines, which are used separately or as needed in combinations or on a regular basis to prevent or reduce symptoms and the frequency of exacerbations. A revolution in the treatment of asthma and COPD occurred thanks to the creation at the end of the last century of long-acting bronchodilators - the α2-agonists salmeterol and formoterol. Today it has been proven that regular therapy with long-acting bronchodilators is more effective and convenient than the use of short-acting bronchodilators [1]. The next step was the creation of drugs for inhalation, which are a combination of ICS and long-acting β2 agonists. Currently, there are two combination drugs containing ICS and a long-acting bronchodilator: salmeterol/fluticasone propionate and formoterol/budesonide (Symbicort). Both are widely and successfully used to treat AD. Indications for the use of these drugs in patients with COPD are limited to the III (severe) stage, which occurs with frequent exacerbations. In Russia and the European Union, Symbicort turbuhaler (formoterol 4.5 mcg + budesonide 80, 160 mcg) is registered as a means of symptomatic treatment of severe COPD; Symbicort 9/320 mcg is expected to appear in Russia soon. A 5-year experience in using combinations of ICS with long-acting bronchodilators in patients with COPD has shown that combination drugs are safe and more effective than their individual components. The results of one of the first comparative studies showed that the use of a combination of formoterol/budesonide (160/4.5 mcg, 2 inhalations 2 times a day) for a year in patients with severe COPD reduced the average number of exacerbations of COPD by 24% per year compared with placebo and by 23% compared with formoterol (4.5 mcg, 2 inhalations 2 times a day). The severity of all symptoms and the need for inhaled short-acting β2-agonists significantly decreased compared to placebo and budesonide (200 mcg, 2 inhalations 2 times a day). FEV1 increased by 15% compared to placebo and by 9% compared to budesonide. Morning peak expiratory flow was significantly improved after the first day of treatment with the combination drug compared to placebo and formoterol, after a week - compared to placebo, formoterol and budesonide, and this advantage was maintained throughout the entire 12-month follow-up. Treatment with formoterol/budesonide significantly improved quality of life scores compared with placebo. There were no significant adverse effects of combination therapy compared with placebo [5]. Another large-scale, long-term study of a similar design, conducted at the same time as the first, also showed clear benefits of the combination of formoterol/budesonide at a dose of 320/9 mcg twice daily compared with placebo, budesonide (400 mcg twice daily). and formoterol (9 mcg 2 times a day) separately. Combination inhalation therapy led to a significantly more significant increase in FEV1, peak expiratory flow before bronchodilator inhalation, improvement in quality of life, reduction in exacerbations of COPD and an increase in the duration of the period until the development of the first exacerbation than the use of its individual components or placebo [6]. A study of the economic feasibility of using the combination of formoterol/budesonide in patients with COPD stages III–IV according to GOLD, conducted in Sweden, showed that the cost of treating 1 patient per year using formoterol/budesonide averaged 2518 euros, budesonide - 3194 euros , formoterol – 3653 euros and placebo – 3213 euros, which clearly indicated in favor of combination therapy [7]. If we take into account the prevalence of COPD throughout the world, the reduction in the frequency of exacerbations of the disease under the influence of effective combination inhaled therapy is even more significant from both clinical and economic points of view [8]. A meta-analysis published in 2007 summarized the results of 11 studies that included 6427 COPD patients. Comparison of the results of using combinations of salmeterol/fluticasone and formoterol/budesonide with placebo showed that combination inhalation therapy helps reduce the frequency of exacerbations of COPD by 1/4, reduce the severity of symptoms, improve functional indicators and improve health status. The increased risk of pneumonia due to combination inhalation therapy requires special study [9]. An assessment of the speed of onset of the bronchodilator effect of salmeterol/fluticasone and formoterol/budesonide in patients with COPD stages II–III revealed a significant advantage of formoterol/budesonide, the effect of which began 5 minutes after inhalation, which was comparable to the speed of onset of the effect of salbutamol [10]. Symbicort in the treatment of patients with a combination of BA and COPD Prolonged course of severe BA leads to remodeling of the airways and the formation of an irreversible component of bronchial obstruction. The development of COPD in a patient with uncontrolled asthma is 12 times more likely than in cases of complete control of asthma. COPD and asthma can be combined, for example, in smoking patients with asthma. The presence of two diseases suggests a mutually aggravating influence of various pathogenetic mechanisms of maintaining chronic inflammation of the respiratory tract, which determines the characteristics of the clinical manifestations and course of the combined pathology. The advisability of using combinations of ICS and long-acting β2-agonists in cases of combined pathology is justified from the point of view of the well-known mechanisms of the pathogenesis of both diseases. It can be assumed that the mutual potentiation of the action of ICS and long-acting β2 agonists is realized due to their interaction at the receptor level [11–13]. Possibility of combinations of ICS and long-acting bronchodilators of various pharmacological groups The feasibility of simultaneous use of long-acting bronchodilators of various pharmacological groups and ICS as basic therapy in patients with severe and extremely severe COPD, as well as in cases of a combination of COPD and severe BA, has not been clearly proven, but this issue deserves attention researchers and practitioners, since the results of a few studies indicate in favor of this combination. The benefit of using a combination of tiotropium and formoterol in patients with severe COPD compared with either drug alone was shown in a study by J. van Noord et al. [14]. The effect of the combination of formoterol and tiotropium on lung function in patients with moderate COPD was more effective than the use of salmeterol/fluticasone [15]. In a study conducted in patients with severe and extremely severe COPD, the addition of tiotropium (18 mcg daily) to a salmeterol/fluticasone combination (50/500 mcg twice daily) significantly increased the effect of treatment on respiratory function. By the end of the third month of the study, FEV1 increased by 140 ml in the group of patients receiving tiotropium, by 141 ml in salmeterol/fluticasone, and by 186 ml in the group receiving a combination of tiotropium and salmeterol/fluticasone [16]. We have not found any reports on the combined use of Symbicort and tiotropium in patients with COPD, but we have our own modest experience in treating patients with a combination of severe COPD and asthma with this combination of drugs [17]. In our patients, long-term inhaled basic therapy with Symbicort and tiotropium allowed us to achieve stable control of bronchial asthma, a noticeable increase in FEV1 and a long-term (up to 2 years) absence of exacerbations of COPD. Conclusion Thus, the accumulated experience in the use of combination inhaled therapy with ICS and long-acting β2-agonists, in particular, the drug Symbicort, in patients with stable severe COPD and in cases of combination of COPD with severe bronchial asthma indicates a significant advantage of combination therapy compared with ICS monotherapy. Long-term basic therapy using Symbicort in these categories of patients can significantly reduce the frequency of exacerbations of COPD, reduce the severity of disease symptoms and improve the quality of life. References 1. Global Initiative for Chronic Obstructive Lung Disease. Revised 2006. 2. Sutherland ER, Martin RJ. Airway inflammation in chronic obstructive pulmonary disease: comparisons with asthma. J. Allergy Clin. Immunol. 2003;112:819–827. 3. Yang IA, Fong KM, Sim EH, et al. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst. Rev. 2007;18:CD002991. 4. Inhaled Corticosteroids for Chronic Obstructive Pulmonary Disease. A Status report. Am. J. Respira. Crit. Care. Med. 2007;175:103–107. 5. Szafranski W., Cukier A., ​​Ramirez A. et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur. Respira. J. 2003;21:74–81. 6. Calverley PM, Boonsawat W., Cseke Z. et al. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur. Respira. J 2003;22:912–919. 7. Lofdahl CG, Ericsson A., Svensson K., Andreasson E. Cost effectiveness of budesonide/formoterol in a single inhaler for COPD compared with each monocomponent used alone. Pharmacoeconomics. 2005;23:365–375. 8. Buist AS, Vollmer WM, Sullivan SD et al. The burden of obstructive lung disease initiative (BOLD): rationale and design. J. COPD. 2005; 2: 277–283. 9. Nannini L., Cates CJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst. Rev. 2007.17;CD003794. 10. Lindberg A., Szalai Z., Pullerits T., Radeczky E. Fast onset of effect of budesonide/formoterol versus salmeterol/fluticasone and salbutamol in patients with chronic obstructive pulmonary disease and reversible airway obstruction. Respirology. 2007;12:732–739. 11. Guerra S. Overlap of asthma and chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2005;11:7–13. 12. Decramer M., Selroos O. Asthma and COPD: differences and similarities. With special reference to the usefulness of budesonide/formoterol in a single inhaler (Symbicort) in both diseases. Int. J. Clin. Pract. 2005;59:385–398. 13. Miller–Larsson A., Selroos O. Advances in asthma and COPD treatment: combination therapy with inhaled corticosteroids and long-acting beta 2 agonists. Curr. Pharm. Dis. 2006;12:3261–3279. 14. van Noord JA, Aumann JL, Janssens E. et al. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest. 2006; 129:509–517. 15. Rabe KF, Timmer W., Sagriotis A., Viel K. Comparison of a combination of tiotropium and formoterol to salmeterol and fluticasone in moderate COPD. Eur. Respira. J. 2005; 26: Suppl. 49:14s. 16. Cazzola M., Ando F., Santus P. et al.. A pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe–to–very severe COPD Pulm. Pharmacol. Ther. 2006:7. 17. Stepanyan I.E. Effective use of tiotropium in complex inhalation therapy of patients with a combination of COPD and asthma. Difficult patient. – 2007; 5:33–36.