Spiolto Respimat® [Olodaterol hydrochloride, tiotropium bromide]

Pharmacological properties

Pharmacodynamics

Mechanism of action. The drug Spiolto Respimate contains two active ingredients: tiotropium, a long acting muscarinic receptor antagonist, and olodaterol, β₂long-acting adrenergic agonist.

The two active ingredients exhibit additional bronchodilating activity through a different mechanism of action. Since it is believed that muscarinic receptors predominate in the central airways, and β₂β-adrenergic receptors have a high level of expression in the peripheral airways, the combination of tiotropium and olodaterol should provide optimal bronchodilating activity in all parts of the lungs.

Tiotropium. Thiotropium bromide is a specific antagonist of long-acting muscarinic receptors. Tiotropium has a similar affinity for M receptor subtypes₁-M₅. In the respiratory tract, tiotropium bromide binds competitively and reversibly to M₃-receptors of bronchial smooth muscles, counteracting the cholinergic (bronchoconstrictive) effect of acetylcholine, which leads to relaxation of bronchial smooth muscles. The effect was dose-dependent and lasted more than 24 hours. Since tiotropium is a bronchoselective N-quaternary anticholinergic, when inhaled, it shows an acceptable therapeutic range until systemic anticholinergic effects appear.

Olodaterol. Olodaterol has high affinity and selectivity for β₂human adrenergic receptors.

In vitro studies have shown that the agonistic activity of olodaterol in relation to β₂-adrenoreceptors 241 times higher activity in relation to β₁-adrenoreceptors and 2299 times to β₃-adrenoreceptors.

Olodaterol acts by binding and activating β₂-adrenoreceptors after topical administration by inhalation.

Β activation₂-adrenoreceptors in the airways leads to the stimulation of intracellular adenylcyclase, which is involved in the synthesis of cyclic 3,5-adenosine monophosphate (cAMP). An increase in cAMP causes bronchodilation, relaxing smooth muscle cells in the airways. Olodaterol is a selective β agonist₂long-acting adrenoreceptors, characterized by a rapid onset of action and prolonged preservation of the effect for at least 24 hours

β-adrenergic receptors are divided into 3 subspecies: β₁-adrenoreceptors, which are localized mainly on the smooth muscles of the heart, β₂-adrenoreceptors - on the smooth muscles of the respiratory tract and β₃adrenergic receptors contained in adipose tissue. β₂-agonists cause bronchodilation. Despite the fact that β₂-adrenoreceptors are the predominant adrenoreceptors in the smooth muscles of the respiratory tract, they are also present on the surface of many other cells, including in the epithelium and endothelium of the lungs and heart. Exact function β₂-receptors in the heart is unknown, but their presence indicates the possibility of influence on the heart of even highly selective β₂-adrenomimetics.

Effect on cardiac electrophysiology

Tiotropium. During a specialized study of the Q – T interval with 53 healthy volunteers of tiotropium at a dose of 18 μg and 54 μg in the form of powder for inhalation (i.e. 3 times the therapeutic dose) for 12 days, it did not cause a significant prolongation of the Q – T interval on the ECG .

Olodaterol. The effect of olodaterol on the Q – T / Q – Tc interval on the ECG was evaluated in 24 healthy volunteers of both sexes in a double-blind, randomized, placebo and actively (moxifloxacin) controlled study. It was found that a single use of olodaterol at doses of 10, 20, 30 and 50 μg led after 20 minutes to 2 hours to increase (compared with placebo) the Q – T interval (compared with the initial value), which increased with an average increase in dose from 1.6 ms (olodaterol at a dose of 10 μg) to 6.5 ms (olodaterol at a dose of 50 μg), with the upper limit of bilateral 90% confidence intervals being 10 ms for all dosages for an individually adjusted Q – T interval (Q – Tc –I).

The effects of olodaterol at a dose of 5 μg and 10 μg on heart rate and heart rate were assessed by continuous 24-hour ECG recording (Holter monitoring) in a subgroup of 772 patients during a 48-week, placebo-controlled phase III study.There were no trends in changes in the frequency of the heart rhythm or the frequency of extrasystoles and their type depending on the dose of the drug or on time. Changes in extrasystoles from baseline to the end of treatment do not indicate a significant difference between olodaterol 5 μg, 10 μg and placebo.

The drug Spiolto Respimate. Two 52-week, randomized, double-blind studies of Spiolto Respimat included 5162 patients with COPD. In a generalized analysis, the number of patients with changes in the Q – Tc – F interval with a adjusted baseline (correction according to the Fridericia formula), which is 30 ms 40 minutes after taking the dose on the 85th, 169th and 365th day, fluctuated in limits of 3.1; 4.7 and 3.6% in the group of taking the drug Spiolto Respimat compared with 4.1; 4.4 and 3.6% in the group receiving olodaterol at a dose of 5 μg and 3.4; 2.3 and 4.6% in the group receiving tiotropium at a dose of 5 μg, respectively.

Clinical efficacy and safety. The Phase III clinical development program for Spiolto Respimat included three randomized, double-blind studies:

• two repeated 52-week studies in parallel groups to compare Spiolto Respimat with tiotropium at a dose of 5 mcg and olodaterol at a dose of 5 mcg (1029 patients received Spiolto Respimat) [studies 1 and 2];
• one 6-week cross-sectional study to compare Spiolto Respimat with 5 mcg tiotropium, 5 mcg olodaterol and placebo (139 patients received Spiolto Respimat) [study 3].

In the course of these studies, comparison drugs, tiotropium at a dose of 5 mcg, olodaterol at a dose of 5 mcg and placebo, were administered via the Respimat inhaler.

Effect on lung function. During a 52-week study, the drug Spiolto Respimat, which was used once a day in the morning, provided a clear improvement in lung function indicators 5 minutes after taking the first dose compared with tiotropium at a dose of 5 μg (average improvement in FEV₁ (forced expiratory volume in the first second)): 0.137 L in the administration group of the drug Spiolto Respimat compared to 0.058 L in the administration group of tiotropium at a dose of 5 μg [p0.0001] and 0.125 L in the administration group of olodaterol at a dose of 5 μg [p = 0.16]).

Both studies showed significant improvement in AUC_0-3h FEV₁ and minimum FEV₁ after 24 weeks (primary criteria for evaluating the effectiveness for pulmonary function) in the administration group of the drug Spiolto Respimat compared with the administration group of tiotropium at a dose of 5 μg and the administration group of olodaterol at a dose of 5 μg.

In patients with a higher degree of recurrence at the initial level, in general, a better bronchodilating reaction to the drug Spiolto Respimat was observed than in patients with a lower degree of recurrence at the initial level.

The bronchodilating effect of the drug Spiolto Respimat compared with tiotropium at a dose of 5 μg and olodaterol at a dose of 5 μg remained during the entire 52-week treatment period. Spiolto Respimat also improved PIC_out (peak volume expiratory flow rate) in the morning and evening, which was determined by the daily records of patients compared with tiotropium at a dose of 5 μg and olodaterol at a dose of 5 μg.

During a 6-week study, the drug Spiolto Respimat caused a significantly greater reaction of FEV₁ compared with tiotropium at a dose of 5 μg, olodaterol at a dose of 5 μg and placebo (p0,0001) for a full 24-hour administration interval.

Quality of life due to health status. The drug Spiolto Respimat showed an improvement in the quality of life due to the state of health, according to the scale of the respiratory questionnaire of St. Georges Hospital (ROBSG). After 24 weeks, there was a statistically significant improvement in the average total score for RBSG in the administration group of the drug Spiolto Respimat compared with the administration group of tiotropium at a dose of 5 μg, in the administration group of olodaterol at a dose of 5 μg; an improvement was observed in all indicators of RBSG.Most patients taking Spiolto Respimat showed a clinically significant improvement in the total RBSG score (MKVO (minimum clinically important difference), defined as a decrease of at least 4 points from the baseline) compared with patients who took tiotropium at a dose of 5 μg ( 57.5% compared to 48.7%, p = 0.0001) and olodaterol at a dose of 5 μg (57.5% compared to 44.8%, p0.0001).

Dyspnea. After 24 weeks of use of the drug, Spiolto Respimat, a greater number of patients significantly decreased the severity of dyspnea compared with the tiotropium administration group at a dose of 5 μg (54.9% compared to 50.6%, p = 0.0546) and the olodaterol administration group at a dose 5 μg (54.9% compared with 48.2%, p = 0.0026).

The use of emergency medicine. Patients taking Spiolto Respimat were less likely to use an emergency drug (salbutamol) during the day and night compared with patients who took tiotropium at a dose of 5 μg and olodaterol at a dose of 5 μg (the average number of cases of using a daily emergency drug in the group of administration Spiolto Respimat is 0.76 cases per day compared to 0.97 cases per day in the tiotropium administration group at a dose of 5 mcg and 0.87 cases per day in the tiotropium administration group at a dose of 5 mcg, p0.0001; average number of cases applied the emergency treatment at night in the Spiolto Respimat administration group is 1.24 cases per day compared with 1.69 cases per day in the tiotropium administration group at a dose of 5 mcg and 1.52 cases per day in the olodaterol administration group at a dose 5 mcg, p0.0001).

Global patient assessment. Patients taking Spiolto Respimat felt a greater improvement in respiratory status compared to patients who took tiotropium at a dose of 5 μg and olodaterol at a dose of 5 μg, as measured by the Global Patient Rating scale.

Aggravation. Tiotropium at a dose of 5 μg previously showed a clinically significant reduction in the risk of developing exacerbations of COPD compared with placebo. COPD exacerbations are included as an additional endpoint during the 52-week main study (study 1 and 2). In the summary database, the proportion of patients who reported at least one case of moderate to severe COPD exacerbation was 27.7% in the group receiving Spiolto Respimat and 28.8% in the group taking tiotropium at a dose of 5 μg (p = 0.39 ) For these studies, a special design has not been developed to assess the impact of treatment on the course of exacerbation of COPD.

Inhalation capacity, degree of difficulty breathing, and physical endurance. The effect of Spiolto Respimat on inspiratory capacity, degree of difficulty in breathing, and maximum physical endurance was investigated during three randomized double-blind studies in patients with COPD [studies 4, 5, and 6].

The drug Spiolto Respimat significantly improved the inspiratory capacity at rest 2 hours after taking the dose compared with tiotropium at a dose of 5 μg (0.114 L, p0.0001, Study 4; 0.088 L, p = 0.0005, Study 5), olodaterol B a dose of 5 μg (0.119 L, p0.0001, study 4; 0.080 L, p = 0.0015, study 5) and placebo (0.244 L, p0.0001, study 4; 0.265 L, p0.0001, study 5) through 6 weeks

During studies 4, 5 and 6, the drug Spiolto Respimat significantly improved endurance time during exercise compared with placebo after 6 weeks (improvement of 20.9%, p0.0001 and 13.4%, p0.0001 in studies 4 and 5 respectively) and 12 weeks (13.8% improvement, p = 0.021; study 6).

Children. The efficacy and safety of Spiolto Respimat in children with COPD have not been established.

Pharmacokinetics When using tiotropium and olodaterol in combination in the form for inhalation, the pharmacokinetic parameters of both components were similar to those that were noted when taking each active component separately.

Thiotropium and olodaterol demonstrate linear pharmacokinetics in the therapeutic range. After repeated inhalations of the drug 1 time per day, the equilibrium state of tiotropium is achieved on the 7th day. The equilibrium state of olodaterol is achieved after 8 days with inhalations 1 time per day, and the degree of exposure increased 1.8 times compared with the use of a single dose.

Absorption

Tiotropium.When inhaled by healthy volunteers of a young age, urinary excretion data show that about 33% of the inhalation dose through the Respimat inhaler enters the systemic circulation. Oral solutions of tiotropium bromide are characterized by absolute bioavailability in the range of 2-3%. The concentration of tiotropium in the blood plasma reaches its maximum level 5-7 minutes after inhalation through the Respimat inhaler.

Olodaterol. In healthy volunteers, after inhalation of the drug, the bioavailability of olodaterol was about 30%, while the bioavailability of olodaterol after oral administration in the form of a solution was 1%. The concentration of olodaterol in blood plasma reaches a maximum level usually within 10-20 minutes after inhalation through a Respimat inhaler.

Distribution. Tiotropium binds to plasma proteins by 72% and is characterized by a distribution volume of 32 l / kg. Studies in rats showed that tiotropium does not penetrate the BBB to a large extent.

Olodaterol is approximately 60% bound to plasma proteins and is characterized by a distribution volume of 1110 liters. Olodaterol is a substrate for P-gp, transporters of accumulation of OAT1, OAT3 and OCT1. Olodaterol is not a substrate for such storage vectors: BCRP, MRP, OATP2, OATP8, OATP-B, OCT2 and OCT3.

Biotransformation

Tiotropium. The degree of biotransformation is low. This is confirmed by urinary excretion of 74% of the drug unchanged after iv administration. Tiotropium as an ether non-enzymatically decomposes to alcohol and acid (N-methylscopic, dithienyl glycolic acid, respectively), which do not bind to muscarinic receptors. Further, in vitro studies on liver microsomes and human hepatocytes, tiotropium (20% of the dose after iv administration) is metabolized by cytochrome P450 (CYP) 2D6 and 3A4 oxidation and subsequent glutathione conjugation with the formation of various phase IIc metabolites.

Olodaterol is largely metabolized by direct glucuronidation and O-demethylation of the methoxylated portion of the molecule, followed by conjugation. Of the 6 identified metabolites with β₂-receptors binds only one unconjugated demethylated derivative. However, this metabolite was not detected in blood plasma after prolonged inhalation use of the drug in the recommended therapeutic dose or in doses exceeding the therapeutic by 4 times. O-demethylation of olodaterol involves cytochrome P450 isoenzymes CYP 2C9 and CYP 2C8 and (to a small extent) CYP 3A4, while isoforms of uridine diphosphate glycosyltransferase, UGT2B1, UGT1A7, 1GT1A7, 1GT1A7, are involved in the formation of olodaterol glucuronides.

Breeding

Tiotropium. The total clearance of tiotropium in healthy volunteers is 880 ml / min. With iv administration of tiotropium, it is mainly excreted unchanged in urine (74%). After inhalation of patients with COPD in equilibrium, excretion in the urine is 18.6% of the dose, the remainder is not absorbed by the intestine and excreted in the feces. Renal clearance of tiotropium exceeds the glomerular filtration rate, which indicates active excretion in the urine. Effective T_½ tiotropia after inhalation of patients with COPD ranged from 27 to 45 hours.

Olodaterol. The total clearance of olodaterol in healthy volunteers is 872 ml / min, and the renal clearance is 173 ml / min. After iv administration [^l4C] -labeled olodaterol 38% of the radioactive dose was detected in urine and 53% in feces. The amount of unchanged olodaterol detected in urine after iv administration was 19%. After ingestion, only 9% of the radioactive dose (0.7% of unchanged olodaterol) was detected in urine, while the main part was detected in feces (84%). More than 90% of the dose was taken after iv administration for 5 days and after oral administration for 6 days. After inhalation of the drug, excretion of unchanged olodaterol in the urine during the dosing interval was 5–7% of the dose in healthy volunteers. Plasma olodaterol concentrations after inhalation are reduced multiphase; terminal T_½ is about 45 hours

Special populations

Tiotropium.It is expected that for all drugs excreted mainly by the kidneys, the elderly patient was associated with a decrease in renal clearance of tiotropium from 347 ml / min in patients with COPD at the age of 65 to 275 ml / min in patients with COPD at the age of ≥65 years. This factor did not lead to a corresponding increase in AUC_0-6,ss or C_max,ss.

Olodaterol. A pharmacokinetic meta-analysis using data obtained from 2 controlled clinical trials involving 405 patients with COPD and 296 patients with AD showed that dose adjustment depending on the patient’s age, gender and body weight is not required, given the systemic effect of olodaterol.

Race

Olodaterol. Comparison of pharmacokinetic data obtained in clinical studies revealed a tendency to a higher systemic effect of olodaterol in the Japanese and other representatives of the Mongoloid race in comparison with patients of the Caucasian race.

In clinical studies of olodaterol, which was used in doses exceeding the recommended therapeutic dose by 2 times, for more than one year, no safety comments were found in patients of the Caucasoid and Mongoloid race.

Renal failure

Tiotropium. After inhalation, tiotropium 1 time per day until equilibrium is obtained in patients with COPD with mild renal impairment (CL_CR 50–80 ml / min) noted a slight increase in AUC_0-6,ss (increase from 1.8 to 30%) and similar C_max,ss compared with patients with normal renal function (creatinine clearance 80 ml / min). In patients with moderate or severe impaired renal function (creatinine clearance of 50 ml / min), iv administration of tiotropium led to a doubling of plasma concentrations (increased AUC_0-4h 82% and C_max 52%) compared with patients with normal renal function, which was confirmed by the results of observations after inhalation of dry powder.

Olodaterol. There was no clinically relevant increase in systemic exposure in patients with impaired renal function.

Liver failure

Tiotropium. Hepatic insufficiency does not significantly affect the pharmacokinetics of tiotropium. Tiotropium is secreted mainly by the kidneys (74% in healthy volunteers) and by simple non-enzymatic cleavage of the ether into inactive products.

Olodaterol. There is no evidence of a difference in olodaterol excretion (as well as protein binding) between patients with mild or moderate hepatic impairment and healthy volunteers. Studies involving patients with severely impaired liver function have not been conducted.

Indications

Supportive bronchodilator therapy to alleviate symptoms in adult patients with the disease.

Application

Mode of application. the drug is intended for inhalation use only. The cartridge can only be used with a respimat inhalation device.

Two breaths with the Respimat inhaler contain one dose.

Adults The recommended dose is 5 mcg tiotropium and 5 mcg olodaterol in the form of two breaths using the Respimat inhaler 1 time per day at the same time of the day.

Do not exceed recommended dose.

Special categories of patients

Elderly patients. Elderly patients can use the drug Spiolto Respimate in the recommended dose.

Impaired liver function and impaired renal function. The drug Spiolto Respimate contains tiotropium, which is excreted mainly by the kidneys, and olodaterol, which is metabolized mainly in the liver.

Impaired liver function. Patients with impaired liver function of mild to moderate severity can use the drug Spiolto Respimat in the recommended dose.

There is no data on the use of olodaterol in patients with severely impaired liver function.

Impaired renal function.Patients with impaired renal function may use the drug Spiolto Respimat in the recommended dose.

For use of the drug in patients with moderate to severe renal impairment (creatinine clearance ≤50 ml / min), see SPECIAL INSTRUCTIONS and PHARMACOLOGICAL PROPERTIES sections.

The drug Spiolto Respimate contains olodaterol. Experience with olodaterol in patients with severe renal impairment is limited.

Mode of application. To ensure proper use of the drug, the doctor or other healthcare professional must demonstrate to the patient how to use the inhaler.

Instructions for the patient on the use and care of the inhaler. Read carefully the instructions for use and care of the inhaler before using Spiolto Respimat.

If the Spiolto Respimat inhaler has not been used for more than 7 days, before use, point it down and press the button 1 time to release the dose.

If the Spiolto Respimat inhaler has not been used for more than 21 days, repeat steps 4–6 “Preparing for first use” until an aerosol cloud appears. Then repeat steps 4–6 3 more times.

Do not touch the puncture element inside the transparent base.

How to care for an inhaler. To clean the mouthpiece, including the metal part inside the mouthpiece, you only need a damp cloth or cloth at least once a week.

Any minimal discoloration of the mouthpiece does not affect the functioning of the Spiolto Respimat inhaler.

If necessary, you can wipe the inhaler from the outside with a damp cloth.

When to buy a new Spiolto Respimat inhaler. Spiolto Respimat inhaler contains 60 breaths (30 doses) when used according to indications (2 breaths 1 time per day).

The dose indicator shows the approximate amount of drug residue. When the indicator reaches the red zone of the scale, this means that the solution remains for about 7 days (14 breaths). It is then necessary to purchase a new inhaler Spiolto Respimat.

As soon as the dose indicator has reached the end of the red scale, the Spiolto Respimat inhaler will be automatically blocked - there are no more doses to release. From now on, it will be impossible to rotate the transparent base.

Not later than 3 months after the first use, the Spiolto Respimate inhaler must be discarded, even if not all the solution has been used.

Preparation of the inhalation device Spiolto Respimat for first use

1. Remove the transparent base. The cap must be closed. Press the fuse and at the same time pull out the transparent base with the other hand.

2. Insert the cartridge. Insert the narrow end of the cartridge into the inhaler. Place the cartridge on a hard surface and press firmly until it clicks into place (until it clicks into place). Do not remove the cartridge after it has been installed in the inhaler.

3. Install a transparent base. Replace the transparent backing until it clicks into place. The transparent base should no longer be removed.

4. Turn around. The cap must be closed. Rotate the transparent base in the direction of the arrows indicated on the label until it clicks (half a turn).

5. Open the cap completely.

6. Click. Point the Spiolto Respimat inhaler down. Press the button to release the dose. Close the cover.

Repeat steps 4–6 until an aerosol cloud appears.

After the aerosol cloud appears, repeat steps 4–6 3 more times.

The Spiolto Respimat inhaler is now ready for use. These steps do not affect the number of available doses. After preparation, the Spiolto Respimat inhaler is designed for 60 breaths (30 doses).

Daily use of the inhaler Spiolto Respimat

1. Turn around. The cap must be closed.

Rotate the transparent base in the direction of the arrows indicated on the label until it clicks (half a turn).

2. Open the cap completely.

3. Click. Take a full slow exhale.Grasp the mouthpiece tightly with your lips without blocking the ventilation hole. Point the inhaler to the back of the throat. While performing a slow deep breath through the mouth, press the dose release button and continue to slowly inhale until it is comfortable. Hold your breath for 10 seconds or as long as it is comfortable.

Repeat steps, turn, open, press to get a total of 2 inhalations.

Close the cap before using the inhaler again.

Children. The drug Spiolto Respimate is not used in children (under the age of 18 years).

Contraindications

Hypersensitivity to active substances or other components of the drug.

Hypersensitivity to atropine or its derivatives, for example to ipratropium or oxytropy, in the anamnesis.

Side effects

Brief information about the safety of the drug. many of these side effects can be attributed to the anticholinergic properties of tiotropium bromide or β2-adrenergic properties of olodaterol.

Summary table of adverse reactions. The incidence of the following adverse reactions that were observed in the group of patients taking tiotropium at a dose of 5 μg / olodaterol at a dose of 5 μg (1302 patients) was calculated on the basis of summary data from 5 active or placebo-controlled clinical studies in parallel groups in patients with COPD with treatment periods of 4 to 52 weeks.

The table shows the adverse reactions that were identified during all clinical studies of the drug Spiolto Respimat, also includes all adverse reactions that were previously reported in the treatment of each of the components of the drug separately.

Criteria for assessing the incidence of adverse reactions: very often (≥1 / 10); often (≥1 / 100–1 / 10); infrequently (≥1 / 1000–1 / 100); rarely (≥1 / 10,000–1 / 1000) very rarely (1/10 000), unknown (impossible to determine from the available data).

¹Adverse events noted against the background of the use of the drug Spiolto Respimat, and not when using each component separately.

Separate adverse reactions. Profile of anticholinergic adverse reactions. During long 52-week clinical trials of Spiolto Respimat, a frequent anticholinergic adverse reaction was dry mouth, which was detected in approximately 1.7% of patients taking Spiolto Respimat and in 2.7 and 1% in the tiotropium dose group 5 mcg and olodaterol administration group at a dose of 5 mcg, respectively. Dry mouth led to cessation of use of the drug in 1 out of 1029 patients (0.1%) who used the drug Spiolto Respimat.

Serious adverse reactions of an anticholinergic nature include glaucoma, constipation, bowel obstruction, including paralytic bowel obstruction and urinary retention.

Profile of β-adrenergic adverse reactions. During long 52-week clinical trials of the drug Spiolto Respimat, frequent β-adrenergic adverse reactions were palpitations, tachycardia and hypertension.

Olodaterol, one of the components of the drug Spiolto Respimat, belongs to the therapeutic class β₂long-acting adrenergic agonists. Therefore, the possibility of the occurrence of the side effects not mentioned above, characteristic of the whole class β, should be taken into account₂-adrenomimetics such as arrhythmia, myocardial ischemia, angina pectoris, arterial hypotension, tremor, nervousness, muscle spasm, fatigue, malaise, hypokalemia, hyperglycemia and metabolic acidosis.

Other categories of patients. Strengthening anticholinergic effects may develop with increasing age.

special instructions

Bah. the drug spiolto respimat should not be used in patients with ba. the efficacy and safety of the drug spiolto respimat in ba have not been investigated.

Acute bronchospasm. The drug Spiolto Respimat n