Spiolto respimat solution for inhalation 2.5 mcg plus 2.5 mcg/dose 4 ml

Spiolto respimat solution for inhalation 2.5 mcg plus 2.5 mcg/dose 4 ml

Compound

1 dose of the drug contains:

olodaterol 2.5 mcg

tiotropium 2.5 mcg

Release form

Inhalation solution dosed in a cartridge complete with the Respimat inhaler.

1 cartridge contains 4 ml of solution for inhalation, which corresponds to 60 inhalation doses (30 therapeutic doses).

pharmachologic effect

Bronchodilator drug.

Olodaterol, a long-acting beta2-adrenergic agonist, and tiotropium bromide, an m-anticholinergic blocker, provide complementary bronchodilation as a result of different mechanisms of action of the active substances and different localization of target receptors in the lungs.

Tiotropium bromide is a long-acting muscarinic receptor antagonist, often called an m-anticholinergic agent in clinical practice. When administered by inhalation, tiotropium bromide has a local selective effect on the bronchi, while in therapeutic doses without causing systemic m-anticholinergic side effects.

Clinical studies found that the drug Spiolto Respimat, used once a day, in the morning led to a rapid (within 5 minutes after the first dose) improvement in lung function. The effect of Spiolto Respimat was superior to that of tiotropium bromide at a dose of 5 mcg and olodaterol at a dose of 5 mcg, used separately.

When using the drug Spiolto Respimat, compared with the use of tiotropium bromide and olodaterol as monotherapy, a more significant bronchodilator effect was achieved, and the peak expiratory volumetric flow rate increased in the morning and evening hours.

Indications for use

Long-term maintenance therapy for patients with COPD, chronic bronchitis, pulmonary emphysema,

reducing airway obstruction and accompanying shortness of breath;

reducing the frequency of exacerbations; improving exercise tolerance and quality of life.

Directions for use and doses

The recommended therapeutic dose is 2 inhalations of a spray from the Respimat inhaler (5 mcg/therapeutic dose of tiotropium bromide and 5 mcg/therapeutic dose of olodaterol) 1 time/day, at the same time of day.

Before using the drug, you must carefully read the instructions for using the inhalation device.

Contraindications

Patients with hypersensitivity to olodaterol, tiotropium bromide or any component of the drug;

patients who have previously had hypersensitivity to atropine or its derivatives, for example ipratropium and oxitropium;

not recommended for use in children under 18 years of age (due to lack of data on effectiveness and safety).

special instructions

The drug Spiolto Respimat should not be used for bronchial asthma. The effectiveness and safety of Spiolto Respimat in bronchial asthma have not been studied.

Spiolto Respimat is not indicated for the treatment of acute episodes of bronchospasm, i.e. as an ambulance.

Caution should be exercised when performing these activities as dizziness or blurred vision may occur.

Storage conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C. Use within 3 months after the first inhalation.

Note

On prescription.

Spiolto® Respimat®

The pharmacokinetics of the combination drug SPIOLTO RESPIMAT are equivalent to the pharmacokinetics of olodaterol and tiotropium bromide used separately.

Olodaterol and tiotropium bromide have linear pharmacokinetics.

Steady-state pharmacokinetics of olodaterol was achieved after 8 days with once-daily dosing, and exposure increased by 1.8-fold compared to a single dose. Steady-state pharmacokinetics of tiotropium bromide when administered once daily was achieved after 7 days.

Suction

Olodaterol is rapidly absorbed; after inhalation of the drug, maximum plasma concentrations are usually achieved within 10-20 minutes. In healthy volunteers after inhalation of the drug, the absolute bioavailability of olodaterol was about 30%. whereas the absolute bioavailability of olodaterol after oral administration as a solution was below 1%.

Thus, the systemic exposure of olodaterol after inhalation administration is mainly realized through absorption in the lungs, and the contribution of the ingested portion of the dose to the systemic exposure is negligible.

After inhalation of a solution of tiotropium bromide, about 33% of the inhalation dose enters the systemic circulation. Absolute bioavailability when taken orally is 2 - 3%. The maximum concentration in plasma is observed 5-7 minutes after inhalation.

Distribution

The binding of olodaterol to plasma proteins is approximately 60%, and the volume of distribution is 1110 l.

The binding of tiotropium bromide to plasma proteins is 72%: volume of distribution is 32 l/kg. Preclinical studies have shown that tiotropium bromide does not penetrate the blood-brain barrier.

Biotransformation

Olodaterol is largely metabolized by direct glucuronidation and O-demethylation followed by conjugation. Of the six identified metabolites, only one unconjugated demethylated derivative (SOM 1522) binds to β2 receptors; however, this metabolite is not detectable in plasma after long-term inhalation use of the drug at the recommended therapeutic dose or at doses 4 times higher than the therapeutic dose. Cytochrome P450 (isoenzymes CYP2C9, CYP2C8 and, to a small extent, CYP3A4) is involved in O-demethylation of olodaterol. The isoforms of uridine diphosphate glycosyltransferase, UGT2B7, UGT1A1, 1A7 and 1A9, are involved in the formation of olodaterol glucuronides.

The degree of biotransformation of tiotropium bromide is insignificant. This is confirmed by the fact that after intravenous administration of tiotropium bromide to young healthy volunteers, 74% of tiotropium bromide is excreted unchanged by the kidneys. Tiotropium bromide is an ester that splits into ethanol-N-methylscopine and dithienylglycolic acid; these compounds do not bind to muscarinic receptors.

In vitro studies have shown that some of the drug (<20% of the dose after intravenous administration) is metabolized by oxidation by cytochrome P450 (CYP2D6 and 3A4) followed by conjugation with glutathione and the formation of various metabolites.

Removal

The total clearance of olodaterol in healthy volunteers is 872 ml/min. and renal clearance is 173 ml/min. The terminal half-life after intravenous use of olodaterol is 22 hours, while the terminal half-life after inhalation use is approximately 45 hours. It follows that in the latter case, elimination is more dependent on absorption.

The total isotopically labeled dose of olodaterol excreted through the kidneys (including the parent compound and all metabolites) was 38% after intravenous administration and 9% after oral administration. The total isotope-labeled dose excreted through the kidneys of unchanged olodaterol was 19% after intravenous administration. The total isotopically labeled dose excreted through the intestine was 53% after intravenous administration and 84% after oral administration.

More than 90% of the drug dose was eliminated after intravenous administration for 5 days and after oral administration for 6 days. After inhalation use of the drug, excretion of unchanged olodaterol by the kidneys during the dosing interval was 5-7% of the dose in healthy volunteers during the period of steady-state pharmacokinetics.

Tiotropium bromide after intravenous administration is mainly excreted unchanged by the kidneys (74%). The total clearance after intravenous administration of tiotropium bromide to young healthy volunteers is 880 ml/min. After inhalation of the solution in patients with COPD, renal excretion is 18.6% (0.93 µt), the remaining unabsorbed portion is excreted through the intestine. The renal clearance of tiotropium bromide exceeds the clearance of creatinine, indicating its tubular secretion. The terminal half-life of tiotropium bromide after inhalation ranges from 27 to 45 hours.

Pharmacokinetics in elderly patients

Clinical studies have shown that despite the influence of age, gender and body weight on the systemic exposure of olodaterol, no dose adjustment is required.

In old age, there is a decrease in the renal clearance of tiotropium (347 ml/min in patients with COPD under the age of 65 years and 275 ml/min in patients with COPD over 65 years of age). However, this did not lead to an increase in the values ​​of AUC0-6,ss and Cmax,ss.

Race

Comparison of pharmacokinetic data obtained in clinical studies of olodaterol. found a trend toward higher systemic exposure to olodaterol in Japanese and other Asian patients compared with Caucasian patients. In clinical studies of olodaterol. administered at doses that were twice the recommended therapeutic dose, no safety concerns were identified in Caucasian and Asian patients.

Patients with burst function disorders

In patients with severe renal failure (creatinine clearance (CC) <30 ml/min), systemic exposure to olodaterol increased by an average of 1.4 times. This increase in exposure does not raise safety concerns based on the experience gained with olodaterol in clinical studies.

After inhaled once-daily administration of tiotropium during steady-state pharmacokinetics in patients with COPD and mild renal failure (creatinine clearance 50-80 ml/min), there was a slight increase in AUC0-6.ss by 1.8-30% and Cmax .ss compared with patients with normal renal function (creatinine clearance >80 ml/min). In patients with COPD and moderate to severe renal impairment (creatinine clearance <50 mL/min), intravenous tiotropium bromide resulted in a twofold increase in total tiotropium bromide exposure (AUC0-4 increased by 82% and Cmax increased by 52% ) compared to patients with normal renal function. A similar increase in plasma concentration was noted after inhalation of the dry powder.

Patients with liver dysfunction

In patients with mild to moderate hepatic impairment, systemic exposure to olodaterol did not change. The systemic effects of olodaterol in patients with severe hepatic impairment have not been studied.

It is assumed that liver failure does not have a significant effect on the pharmacokinetics of tiotropium bromide, since tiotropium bromide is primarily excreted by the kidneys and by non-enzymatic cleavage of the ester bond to form derivatives that do not have pharmacological activity.

Scientific results of biomedical research

Introduction. “Chronic obstructive pulmonary disease (COPD) is one of the most common respiratory diseases” [3, 5]. A characteristic feature of this disease is progressive bronchial obstruction, which determines the severity and development of complications [1, 8]. In recent years, there has been an increase in clinically severe forms of COPD with the development of pulmonary heart failure, which leads to disability and premature death.

One of the most important consequences of bronchial obstruction “is pulmonary hypertension (PH), which significantly affects the course of the disease” [3, 5]. Chronic cor pulmonale, often observed in the 2nd stage of COPD and almost always complicating the 3rd stage [4, 9] of the disease, is a natural result of long-term PH. 84% of COPD patients die from decompensated heart failure as a consequence of PH. The leading pathogenetic link in hemodynamic disorders in the pulmonary circulation is obstructive changes in ventilation.

Currently, there is no consensus on the advisability of systematic use of antihypertensive drugs to reduce LH levels [6, 7, 12]. At the same time, bronchodilators occupy a central place in the basic therapy of COPD. The effectiveness of their use largely depends on the completeness of delivery to the respiratory system, taking into account violations of the ventilation functions of the lungs [4, 10, 11], which is the basis for modifying delivery methods (use of the Respimat device).

The effect of bronchodilator therapy with Spiolto Respimat on the level of pressure in the pulmonary artery remains insufficiently studied.

Purpose of the study: to study the effects of the most common combination of inhaled bronchodilators β2-agonists (olodaterol) and anticholinergic drugs (tiotropium bromide) on PH in patients with COPD with long-term use.

Materials and methods of research. We examined 30 patients with stage 2-3 COPD who had not previously received constant basic therapy with bronchodilators.

“The diagnosis of COPD was made based on the criteria of the GOLD program (2013) and the Federal COPD program” [3, 5]. An important condition for including patients in the study was the presence of PH (more than 30 mm Hg, mean pressure in the pulmonary artery).

The examination of patients consisted of 2 stages: 1st to identify people with PH - screening, 2nd to solve the main objectives of the study - main. A physical examination was performed at baseline. Then a complete blood and sputum test, ECG, chest radiography, FDV with bronchodilator tests, and echocardiography were studied.

After diagnosis of COPD and detection of PH, patients were included in the study. Patients received continuous maintenance therapy with a long-acting β2-agonist and an anticholinergic drug in the form of a fixed combination (olodaterol + tiotropium bromide, 0.0025 mg + 0.0025 mg, dosed solution for inhalation with a special device (Spiolto Respimat)) - 2 doses 1 time per day for 24 weeks.

The clinical examination of the patient included anamnesis (assessment of disease duration, smoking index) and an objective examination of the patient. Smoking index (SI) - the number of pack-years was determined according to the formula: SI = (number of cigarettes smoked per day x smoking experience): 20.

The clinical picture of the disease (the presence and severity of cough, the nature of sputum, shortness of breath, auscultation pattern in the lungs) was calculated using a score for the severity of these symptoms.

“Evaluation of symptom severity in points:

• Shortness of breath: 0 points – no symptom; 1 point – minimal manifestation of the symptom, unlimited activity; 2 points – pronounced manifestation of the symptom, limiting activity; 3 points – the symptom severely limits activity.
• Cough: 0 points – no symptom; 1 point – only in the morning; 2 points – rare episodes (2-3) during the day; 3 points – frequent (more than 3 times) during the day.
• Wheezing: 0 points – no symptom; 1 point – single, constant; 3 points – multiple, constant.
• Amount of sputum discharge: 0 points – none; 1 point – meager amount, constant; 3 points – moderate amount (up to 50 ml) during the day; 4 points – more than 50 ml during the day.
• Nocturnal suffocation: 0 points – no symptom; 1 point – sometimes; 2 points – 1 time per week; 3 points – daily” [5].

Spirometry was performed using a Master Lab apparatus (Erich Yeager). We assessed the following parameters: forced inspiratory volume in 1 s (FEV), FEV/FVC ratio - Tiffno test, forced vital capacity (FVC), vital capacity (VC), peak expiratory flow 50 and 25 (MSV50, MSV25). The bronchodilator test was carried out according to the ERS criteria (three reproducible attempts with 200 mcg of Salbutamol were evaluated).

The electrocardiogram was performed in 12 standard leads.

Doppler echocardiogram was performed using a Konton Sigma4 device. “The following parameters were determined: mean pressure in the pulmonary artery (Pap), aorta (AO), left atrium (LA), end-diastolic volume of the left ventricle (EDV), end-systolic volume of the left ventricle (ESV), end-diastolic size (EDV), end systolic size (ESD), right ventricular size (RV), right atrium size (RA), left ventricular posterior wall (LPW), interventricular septal thickness (IVS), left ventricular ejection fraction (LVEF)” [5].

Laboratory blood tests included a complete blood count and sputum analysis.

X-ray of the lungs was performed in frontal and lateral projections.

To assess the quality of life of patients (subjective assessment of well-being and satisfaction), the WHO WHOQOL-100 questionnaire (self-completion option) was used. The comparison group for quality of life included 20 healthy people without bad habits (tobacco, hookah smoking).

Monitoring for adverse events was conducted throughout the study.

Data comparisons were made using a paired t test. A p value of <0.5 was considered statistically significant. Data processing was carried out using the SPSS-11 program in Windows XP.

Results and discussion.

At the first stage of the study, out of 30 patients with COPD, 26 had an increase in mean pressure in the pulmonary artery PLA of more than 30 mm Hg. Art. These patients were included in the further study. Of these, 20 were men and 6 were women, aged from 44 to 74 years. The average age was 60.4 ± 1.5 years. The duration of the disease ranged from 3 to 12 years, averaging 8.6 ± 1.4 years. The smoking index ranged from 4 to 80 pack-years, averaging 37.4 ± 5.3 pack-years. Of the concomitant diseases, 10 people had arterial hypertension, 3 had atherosclerotic cardiosclerosis, which were in a compensated state.

An X-ray examination of the chest organs in the vast majority of patients showed changes in the lungs and in the heart and blood vessels. X-ray changes in the lungs were observed in 70% of patients. Most often (in 60% of cases) signs of pulmonary emphysema were recorded, respectively, a low state of the dome of the diaphragm. Quite often, in 1/3 of the patients, an increase in the pulmonary pattern was detected, however, compaction of the roots of the lungs and diffuse pneumosclerosis were detected in a small number of patients. Also, pleural adhesions were detected in 4 patients. In 9 patients, no changes in the lungs were detected during X-ray examination.

When analyzing the identified changes in the heart and blood vessels, the most common were thickening and lengthening of the aorta (40% of patients) and enlargement of the left ventricle (33%), which can be explained, first of all, by the older age group of patients and the presence of concomitant cardiovascular diseases ( in particular arterial hypertension). In 1/5 of the patients, X-ray examination revealed signs of cor pulmonale. However, in 33% of patients no changes in the heart and large vessels were detected during X-ray examination.

The data obtained confirm the insufficient information content of the X-ray examination method in patients with COPD, as well as for identifying pulmonary hypertension in this category of patients.

Electrocardiographic studies revealed no significant changes in the patients included in the study. The most frequently recorded LV hypertrophy and sinus tachycardia (33% of cases), which is explained by the presence of concomitant diseases and the existing pathological process. ECG signs of increased pressure in the pulmonary artery and/or right heart in the form of RA hypertrophy, changes in the electrical axis of the heart, and right bundle branch block were observed in half of the patients.

Changes in the main clinical signs of COPD during 24 weeks of systematic use of Spiolto Respimat with an initial score of 7.5 ± 0.3. After 4 weeks of constant bronchodilator therapy, the condition of the patients improved significantly - cough, shortness of breath, and wheezing in the lungs decreased, which were detected in a smaller number of patients. The average score decreased to 4.4±0.4 (p<0.05). With continuation of constant therapy with olodaterol + tiotropium bromide, a further improvement in general well-being and a decrease in the manifestations of the main symptoms of the disease were determined, which was reflected in a further decrease in the total score of clinical symptoms to 3.2 ± 0.4 after 12 weeks and to 1.6 ± 0.3 after 24 weeks of treatment (p<0.05).

Blood and urine tests (at the beginning and end of the study) did not reveal significantly significant changes.

The results of the study of pulmonary function are presented in Table 1.

Table 1

FDV indicators in patients with COPD during the use of Spiolto Respimat

Table 1

Parameters of PDE in patients with COPD while using Spiolo Respimat

Initial FDV indicators indicated the severity of obstruction, which is typical for patients with stage 3 COPD who have not previously received systematic treatment. After 4 weeks of treatment with olodaterol + tiotropium, the following changes in functional indicators occurred: an increase in FVC to 83.0±4.1%, VC to 79.0±3.5 (p<0.05, compared to baseline values), FEV1 to 58.3±3.3% of the expected value. The value of such indicators as PSV and MSV50 also increased statistically significantly.

After 12 weeks of treatment, the achieved improvement in external respiratory functions was maintained: vital capacity – 77.8±3.1%, FVC – 80.5±3.0, FEV1 – 57.9±2.9%, PEF – 60.0±2 .9% (p<0.05, compared with initial values). It was possible to reach a plateau in changes in functional parameters, however, when studying FDV after 24 weeks of continuous use of Spiolto, further improvement in bronchial patency continued. Thus, vital capacity increases to 83.6±2.8%, FVC – to 87.2±3.0, FEV1 – to 66.6±2.5%, PEF – to 63.8±3.1%. Noteworthy is the increase in PVS by 19.2±2.7%. Interestingly, after 24 weeks of treatment, the FEV1/FVC ratio also increased to statistically significant levels.

The need for constant and adequate use of combined inhaled bronchodilator therapy is emphasized once again by the data obtained. It turns out to be quite effective even in people who have not previously systematically received basic bronchodilator therapy (despite the long period (8.6 ± 1.4 years) of the existence of the disease before the start of systematic treatment and the possible formation of irreversible changes).

During an echocardiographic study, the initial mean pressure in the pulmonary artery PLA was increased to 32.4±0.8 mm Hg. Art. There were no significant changes in other echo CG parameters (Table 2). After 12 weeks of regular use of bronchodilator therapy with Spiolto, the average Pla decreased to 25.8±0.9 (p<0.05). After 24 weeks of treatment, determination of the average Pla showed a further decrease to 23.3±1.2 (p<0.05). Continued research is needed to elucidate the causes and mechanisms of the reduction after 24 weeks of CRA.

table 2

Changes in echocardiogram in patients with COPD with long-term use of Spiolto Respimat

Table 2

Changes in the echocardiogram in patients with COPD with prolonged use of Spiolo Respimat

Thus, the use of regular long-term bronchodilator therapy in patients with COPD leads to a decrease in LH.

Unlike healthy people, the quality of life of patients with COPD was initially impaired on scales characterizing the level of dependence, the sphere of physical and psychological health.

After treatment for 3 months, it was obvious that bronchodilator therapy with Spiolto led to a significant decrease in the dependence on drugs and medical care from 42.7 + 2.8 to 36.8 + 3.7 (p < 0. 01). The value of the physical sphere parameters increased from 43.8 + 2.1 to 46.7 + 3.2 (p < 0.08) and the psychological sphere from 50.8 + 3.4 to 52.5 + 2.1 ( p < 0.1). Patients became more active, sleep and quality of life improved.

Conclusion

Regular combined bronchodilator therapy using Spiolto Respimat effectively reduces pressure in the pulmonary artery in patients with COPD, significantly improved the quality of life (assessed using the method recommended by WHO) and can be recommended for inclusion in their treatment protocols.