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Spiolto Respimat inhalation solution 2.5 mcg/ing + 2.5 mcg/ing Respimat inhaler cartridge 4 ml 60 inhalations

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Spiolto Respimat inhalation solution 2.5 mcg/ing + 2.5 mcg/ing Respimat inhaler cartridge 4 ml 60 inhalations
Spiolto Respimat inhalation solution 2.5 mcg/ing + 2.5 mcg/ing Respimat inhaler cartridge 4 ml 60 inhalations
Spiolto Respimat inhalation solution 2.5 mcg/ing + 2.5 mcg/ing Respimat inhaler cartridge 4 ml 60 inhalations
Spiolto Respimat inhalation solution 2.5 mcg/ing + 2.5 mcg/ing Respimat inhaler cartridge 4 ml 60 inhalations
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1 933.25 грн.
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Active ingredient:Tiotropium, Olodaterol
ATC code:R RESPIRATORY SYSTEM AGENTS; R03 DETERGENTS FOR THE TREATMENT OF OBSTRUCTIVE AIRWAY DISEASES; R03A ADRENERGIC INHALED MEDICINES; R03A L Adrenergic agents in combination with anticholinergic agents; R03A L06 Olodaterol and tiotropium bromide
Country of manufacture:Germany
Form:Liquids
Method of application:For administration into the lungs
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Spiolto Respimat inhalation solution 2.5 mcg/ing + 2.5 mcg/ing Respimat inhaler cartridge 4 ml 60 inhalations
1 933.25 грн.
Description

Instructions Spiolto Respimat inhalation solution 2.5 mcg/ing + 2.5 mcg/ing cartridge with inhaler Respimat 4 ml 60 inhalations

Composition

active ingredients: tiotropium, olodaterol;

1 inhalation contains 2.5 mcg of tiotropium (as bromide monohydrate), 2.5 mcg of olodaterol (as hydrochloride);

Excipients: benzalkonium chloride, disodium edetate dihydrate, purified water, 1M hydrochloric acid.

Dosage form

Solution for inhalation.

Main physicochemical properties: clear, colorless solution for inhalation.

Pharmacotherapeutic group

Drugs for the treatment of obstructive airway diseases. Adrenergic agents in combination with anticholinergics.

ATX code R03AL06.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

The drug SPIOLTO RESPIMAT

SPIOLTO RESPIMAT is a fixed-dose combination medicine (inhalation solution) containing two active ingredients: tiotropium, a long-acting muscarinic receptor antagonist, and olodaterol, a long-acting β2-adrenomimetic (LAMA/LABA) and is delivered via the SPIOLTO RESPIMAT liquid inhaler.

The two active ingredients have additive bronchodilator activity due to different mechanisms of action. As muscarinic receptors are thought to predominate in the central airways and β2-adrenergic receptors are thought to have higher expression levels in the peripheral airways, the combination of tiotropium and olodaterol should provide optimal bronchodilator activity in all parts of the lung.

Tiotropium

Tiotropium bromide is a specific, long-acting muscarinic receptor antagonist. Tiotropium has similar affinity for the M1–M5 receptor subtypes. In the airways, tiotropium bromide competitively and reversibly binds to M3 receptors on bronchial smooth muscle, antagonizing the cholinergic (bronchoconstrictor) effects of acetylcholine, resulting in bronchial smooth muscle relaxation. The effect was dose-dependent and lasted for more than 24 hours. As tiotropium is a locally bronchoselective N-quaternary anticholinergic, it exhibits an acceptable therapeutic range before systemic anticholinergic effects occur when inhaled.

Olodaterol

Olodaterol has high affinity and selectivity for human β2-adrenergic receptors.

In vitro studies have shown that the agonist activity of olodaterol at β2-adrenoceptors is 241 times greater than the activity at β1-adrenoceptors and 2299 times greater than the activity at β3-adrenoceptors.

Olodaterol exerts its pharmacological action by binding to and activating β2-adrenergic receptors following topical administration by inhalation.

Activation of β2-adrenoceptors in the airways leads to stimulation of intracellular adenyl cyclase, an enzyme involved in the synthesis of cyclic 3,5-adenosine monophosphate (cAMP). Increased cAMP levels cause bronchodilation by relaxing smooth muscle cells in the airways. Olodaterol is a selective, long-acting β2-adrenoceptor agonist with a preclinical profile, characterized by a rapid onset of action and a prolonged duration of effect of at least 24 hours.

β-Adrenergic receptors are divided into 3 subtypes: β1-adrenergic receptors, which are localized mainly on the smooth muscle of the heart, β2-adrenergic receptors on the smooth muscle of the airways, and β3-adrenergic receptors found in adipose tissue. β2-agonists cause bronchodilation. Although the β2-adrenergic receptor is the predominant adrenergic receptor in the smooth muscle of the airways, it is also present on the surface of many other cells, including the epithelium and endothelium of the lungs and heart. The exact function of β2-receptors in the heart is unknown, but their presence indicates the possibility of cardiac effects even for highly selective β2-adrenergic agonists.

Impact on cardiac electrophysiology

Tiotropium

In a dedicated QT study in 53 healthy volunteers, tiotropium at doses of 18 mcg and 54 mcg as an inhalation powder (i.e. three times the therapeutic dose) for 12 days did not cause significant prolongation of the QT interval on the ECG.

Olodaterol

The effects of olodaterol 5 mcg and 10 mcg on heart rate (HR) and rhythm were assessed using continuous 24-hour ECG recording (Holter monitoring) in a subset of 772 patients in a 48-week, placebo-controlled phase III trial. There were no trends in heart rate or extrasystoles frequency and type with dose or time. Changes in extrasystoles from baseline to the end of treatment did not indicate a significant difference between olodaterol 5 mcg, 10 mcg and placebo.

The drug SPIOLTO RESPIMAT

In two 52-week, randomized, double-blind trials of SPIOLTO RESPIMAT, 5,162 patients with COPD participated. In the pooled analysis, the number of patients with baseline-corrected QTcF changes (Fridericia correction) > 30 msec at 40 minutes post-dose on days 85, 169, and 365 ranged from 3.1%, 4.7%, and 3.6% in the SPIOLTO RESPIMAT group compared to 4.1%, 4.4%, and 3.6% in the olodaterol 5 mcg group and 3.4%, 2.3%, and 4.6% in the tiotropium 5 mcg group, respectively.

Clinical efficacy and safety

The Phase III clinical development program for SPIOLTO RESPIMAT included three randomized, double-blind trials:

two 52-week, parallel-group, repeated-dose studies comparing SPIOLTO RESPIMAT with tiotropium 5 mcg and olodaterol 5 mcg (1,029 patients received SPIOLTO RESPIMAT) [Studies 1 and 2];

one 6-week crossover study comparing SPIOLTO RESPIMAT with tiotropium 5 mcg, olodaterol 5 mcg and placebo (139 patients received SPIOLTO RESPIMAT) [study 3].

In these studies, the comparators, tiotropium 5 mcg, olodaterol 5 mcg and placebo, were administered via the RESPIMAT inhaler.

Patient characteristics

The majority of the 5162 patients who participated in the 52-week trials worldwide [Studies 1 and 2] were male (73%), Caucasian (71%) or Asian (25%), and had a mean age of 64 years. The mean post-bronchodilator FEV1 was 1.37 L (GOLD 2 [50%], GOLD 3 [39%], GOLD 4 [11%]). The mean β2-agonist sensitivity was 16.6% of baseline (0.171 L). Pulmonary medications permitted as concomitant therapy included inhaled steroids [47%] and xanthines [10%.]

The 6-week trials [Study 3] were conducted in Europe and North America. The majority of the 219 study participants were male (59%), Caucasian (99%), and had a mean age of 61.1 years. The mean post-bronchodilator FEV1 was 1.55 L (GOLD 2 [64%], GOLD 3 [34%], GOLD 4 [2%]). The mean β2-agonist sensitivity was 15.9% of baseline (0.193 L). Pulmonary medications permitted as concomitant therapy included inhaled steroids [41%] and xanthines [4%.]

Impact on lung function

In a 52-week trial, SPIOLTO RESPIMAT administered once daily in the morning provided significant improvements in lung function 5 minutes after the first dose compared with tiotropium 5 mcg (mean improvement in FEV1: 0.137 L in the SPIOLTO RESPIMAT group compared with 0.058 L in the tiotropium 5 mcg group [p < 0.0001] and 0.125 L in the olodaterol 5 mcg group [p = 0.16]).

In both studies, significant improvements were observed in AUC0-3h FEV1 and trough FEV1 (forced expiratory volume in one second) at 24 weeks (primary efficacy endpoints for lung function) in the SPIOLTO RESPIMAT group compared to tiotropium 5 mcg and olodaterol 5 mcg groups (Table 1).

Table 1

Difference between AUC0-3h FEV1 and trough FEV1 in the SPIOLTO RESPIMAT group compared to tiotropium 5 mcg and olodaterol 5 mcg groups at 24 weeks (Studies 1 and 2)

Comparison drug AUC0-3h FEV1 parameters Minimum FEV1 values
Study 1 Study 2 Study 1 Study 2
n Average value n

Average

value

n Average value n Average value
SPIOLTO RESPIMAT 522 502 521 497
Tiotropium 5 mcg 526 0.117 l 500 0.103 l 520 0.071 l 498 0.050 l
Olodaterol 5 mcg 525 0.123 l 507 0.132 l 519 0.082 l 503 0.088 l

Baseline FEV1 before treatment: Study 1 - 1.16 L; Study 2 - 1.15 L.

p ≤ 0.0001 for all comparisons.

n is the number of patients.

The enhanced bronchodilator effect of SPIOLTO RESPIMAT compared to tiotropium 5 mcg and olodaterol 5 mcg was maintained throughout the 52-week treatment period. SPIOLTO RESPIMAT also improved morning and evening PEV as measured by patient daily records compared to tiotropium 5 mcg and olodaterol 5 mcg.

In the 6-week study, SPIOLTO RESPIMAT produced a significantly greater FEV1 response compared to tiotropium 5 mcg, olodaterol 5 mcg, and placebo (p < 0.0001) over the entire 24-hour dosing interval (Table 2).

Table 2

Mean FEV1 (L) difference at 3 hours, 12 hours and 24 hours and difference in trough FEV1 (L) for SPIOLTO RESPIMAT compared to tiotropium 5 μM, olodaterol 5 μM and placebo at 6 weeks (Study 3)

Comparison drug n 3 h average value n 12 h average value 24 hour average1 Minimum value
SPIOLTO RESPIMAT 138 138
Tiotropium 5 mcg 137 0.109 135 0.119 0.110 0.079
Olodaterol 5 mcg 138 0.109 136 0.126 0.115 0.092
Placebo 135 0.325 132 0.319 0.280 0.207

The initial FEV1 level before treatment is 1.30 l.

1 Primary endpoint.

p ≤ 0.0001 for all comparisons.

n = number of patients.

Dyspnea

At 24 weeks (Studies 1 and 2), the mean central score of the dynamic dyspnea index (DDI) was 1.98 units in the SPIOLTO RESPIMAT group, with significant improvement compared to the tiotropium 5 mcg group (mean difference 0.36, p = 0.008) and the olodaterol 5 mcg group (mean difference 0.42, p = 0.002).

More patients treated with SPIOLTO RESPIMAT achieved a clinically meaningful improvement in the DID score “minimum clinically important difference (MICD)”, defined as a value of at least 1 unit, compared to the tiotropium 5 mcg group (54.9% vs. 50.6%, p = 0.0546) and the olodaterol 5 mcg group (54.9% vs. 48.2%, p = 0.0026).

Use of emergency medication

Patients taking SPIOLTO RESPIMAT used less daytime and nighttime rescue medication (salbutamol) compared to patients taking tiotropium 5 mcg and olodaterol 5 mcg (mean number of daytime rescue medication uses in the SPIOLTO RESPIMAT group was 0.76 per day compared to 0.97 per day in the tiotropium 5 mcg group and 0.87 per day in the olodaterol 5 mcg group, p < 0.0001; mean number of nighttime rescue medication uses in the SPIOLTO RESPIMAT group was 1.24 per day compared to 1.69 per day in the tiotropium 5 mcg group and 1.52 per day in the olodaterol group, p < 0.0001). 5 μg dose, p < 0.0001) (Studies 1 and 2).

Global patient assessment

Patients receiving SPIOLTO RESPIMAT experienced greater improvement in respiratory status compared to patients receiving tiotropium 5 mcg and olodaterol 5 mcg, as measured by the Patient Global Assessment Scale (Studies 1 and 2).

Aggravation

Tiotropium 5 mcg has previously been shown to reduce the risk of COPD exacerbations compared to placebo. COPD exacerbations were included as a secondary endpoint in the 52-week pivotal studies (Studies 1 and 2). In the pooled data, the proportion of patients who experienced at least one moderate/severe COPD exacerbation was 27.7% in the SPIOLTO RESPIMAT group and 28.8% in the tiotropium 5 mcg group (p=0.39). These studies were not specifically designed to assess the effect of treatment on the course of COPD exacerbations.

A one-year, randomised, double-blind, active-controlled, parallel-group clinical trial (Study 9) compared the effects of SPIOLTO RESPIMAT and tiotropium 5 mcg on COPD exacerbations. All respiratory medications, such as short-acting beta-agonists, inhaled corticosteroids and xanthines, were permitted as concomitant therapy, except anticholinergics, long-acting beta-agonists and combinations thereof. The primary endpoint was the annual rate of moderate to severe COPD exacerbations (3939 patients treated with SPIOLTO RESPIMAT and 3941 patients treated with tiotropium 5 mcg).

The majority of patients were male (71.4%) and Caucasian (79.3%). The mean age was 66.4 years, the mean post-bronchodilator FEV1 was 1.187 L (SD 0.381), and 29.4% of patients had a history of clinically significant cardiovascular disease.

Treatment with SPIOLTO RESPIMAT resulted in a 7% reduction in the annual rate of moderate to severe COPD exacerbations compared with tiotropium 5 mcg (hazard ratio (HR) 0.93, 99% confidence interval (CI), 0.85–1.02, p = 0.0498). The study did not reach the pre-specified significance level of p < 0.01.

Health-related quality of life

SPIOLTO RESPIMAT improved health-related quality of life as measured by the St. George's Hospital Respiratory Questionnaire (SRQQ). At 24 weeks (Studies 1 and 2), there was a statistically significant improvement in the mean total score of the SRQQQ in the SPIOLTO RESPIMAT group compared to the tiotropium 5 mcg group and the olodaterol 5 mcg group (Table 3); improvements were observed in all SRQQQ measures. More patients receiving SPIOLTO RESPIMAT had a clinically meaningful improvement in the ROLSG total score (MCVD (minimum clinically important difference), defined as a reduction of at least 4 points from baseline, compared to patients receiving tiotropium 5 mcg (57.5% vs. 48.7%, p = 0.0001) and olodaterol 5 mcg (57.5% vs. 44.8%, p < 0.0001).

Table 3

Total ROLSG score after 24 weeks of treatment (Studies 1 and 2)

n

Treatment Average value

(change from baseline)

Difference with respect to Spiolto Respimat
Average (p-value)
Total score Initial level 43.5
SPIOLTO RESPIMAT 979 36.7 (-6.8)
Tiotropium 5 mcg 954 37.9 (-5.6) 1.23 (p=0.025)
Olodaterol 5 mcg 954 38.4 (-5.1) 1.69 (p=0.002)

n is the number of patients.

In two additional 12-week placebo-controlled clinical trials (Studies 7 and 8), the ROLSG total score at 12 weeks was also included as a primary endpoint for assessing health-related quality of life.

In the 12-week studies, SPIOLTO RESPIMAT demonstrated improvements compared to placebo at week 12 in the mean total ROLSG score (primary endpoint) of -4.9 (95% CI: -6.9, -2.9; p < 0.0001) and -4.6 (95% CI: -6.5, -2.6; p < 0.0001). In a pooled supportive analysis of the 12-week studies, the proportion of patients with a clinically meaningful reduction in ROLSG total score (defined as a decrease of at least 4 units from baseline) at week 12 was greater in the SPIOLTO RESPIMAT group (52% [206/393]) compared to tiotropium 5 mcg (41% [159/384]; odds ratio: 1.56 (95% CI: 1.17, 2.07), p = 0.0022) and placebo (32% [118/370]; odds ratio: 2.35 (95% CI: 1.75, 3.16), p < 0.0001).

Inspiratory capacity, degree of difficulty breathing, and physical endurance

The effect of SPIOLTO RESPIMAT on inspiratory capacity, breathlessness and maximal symptom-limited exercise capacity was investigated in three randomised, double-blind studies in patients with COPD:

two repeated 6-week crossover studies comparing SPIOLTO RESPIMAT with tiotropium 5 mcg, olodaterol 5 mcg and placebo in continuous cycling (450 patients received SPIOLTO RESPIMAT) [Studies 4 and 5];

one 12-week parallel group study comparing SPIOLTO RESPIMAT with placebo during cycling exercise (139 patients received SPIOLTO RESPIMAT) and continuous speed walking (subgroup of patients) [study 6].

SPIOLTO RESPIMAT significantly improved resting inspiratory capacity two hours after dosing compared to tiotropium 5 mcg (0.114 L, p < 0.0001; Study 4, 0.088 L, p = 0.0005; Study 5), olodaterol 5 mcg (0.119 L, p < 0.0001; Study 4, 0.080 L, p = 0.0015; Study 5) and placebo (0.244 L, p < 0.0001; Study 4, 0.265 L, p < 0.0001; Study 5) at 6 weeks.

In Studies 4 and 5, SPIOLTO RESPIMAT significantly improved cycling endurance time compared to placebo at 6 weeks (Study 4: geometric mean endurance time 454 seconds with SPIOLTO RESPIMAT compared to 375 seconds with placebo (20.9% improvement, p < 0.0001); Study 5: geometric mean endurance time 466 seconds with SPIOLTO RESPIMAT compared to 411 seconds with placebo (13.4% improvement, p < 0.0001).

In Study 6, SPIOLTO RESPIMAT significantly improved cycling endurance time compared to placebo at 12 weeks (geometric mean endurance time 528 seconds with SPIOLTO RESPIMAT compared to 464 seconds with placebo (13.8% improvement, p=0.021).

Children

The European Medicines Agency has waived the obligation to submit the results of studies with SPIOLTO RESPIMAT in all subsets of children with chronic obstructive pulmonary disease (COPD) in accordance with the decision to waive the obligation to submit studies (see section “Method of administration and dosage”).

Pharmacokinetics.

When tiotropium and olodaterol were administered in combination in an inhaled form, the pharmacokinetic parameters of both components were similar to those observed when each active component was administered separately.

Tiotropium and olodaterol exhibit linear pharmacokinetics in the therapeutic range. After repeated once-daily inhalations, steady-state tiotropium is reached by day 7. Steady-state olodaterol is reached by day 8 with once-daily inhalations, and the extent of exposure is 1.8-fold greater than that after a single dose.

General characteristics of the active substance after administration of the medicinal product

Absorption

Tiotropium. When inhaled by healthy young volunteers, urinary excretion data show that approximately 33% of the inhaled dose via the RESPIMAT inhaler reaches the systemic circulation. Oral solutions of tiotropium bromide have an absolute bioavailability of 2-3%. Tiotropium plasma concentrations reach their maximum levels 5-7 minutes after inhalation via the RESPIMAT inhaler.

Olodaterol: In healthy volunteers, the absolute bioavailability of olodaterol after inhalation was approximately 30%, while the absolute bioavailability of olodaterol after oral administration of the drug as a solution was less than 1%. Olodaterol plasma concentrations reach their maximum level usually within 10-20 minutes after inhalation via the RESPIMAT inhaler.

Distribution

Tiotropium is 72% bound to plasma proteins and has a volume of distribution of 32 l/kg. Studies in rats have shown that tiotropium does not cross the blood-brain barrier to any significant extent.

Olodaterol is approximately 60% bound to plasma proteins and has a volume of distribution of 1110 L. Olodaterol is a substrate for P-gp, the efflux transporters OAT1, OAT3 and OCT1. Olodaterol is not a substrate for the following efflux transporters: BCRP, MRP, OATP2, OATP8, OATP-B, OCT2 and OCT3.

Biotransformation

Tiotropium. The extent of biotransformation is low. This is confirmed by the urinary excretion of 74% of the drug unchanged after an intravenous dose. Tiotropium as an ester is non-enzymatically degraded to an alcohol and an acid (N-methylscopine, dithienylglycolic acid, respectively), which do not bind to muscarinic receptors. Further, in vitro studies in human liver microsomes and hepatocytes indicate that tiotropium (< 20% of the dose after intravenous administration) is metabolized by cytochrome P450 (CYP) 2D6 and 3A4-dependent oxidation and subsequent glutathione conjugation to various phase II metabolites.

Olodaterol is extensively metabolised by direct glucuronidation and O-demethylation of the methoxylated moiety followed by conjugation. Of the six identified metabolites, only one unconjugated demethylated derivative binds to β2 receptors. However, this metabolite is not detected in plasma after prolonged inhalation of the drug at the recommended therapeutic dose or at doses exceeding the therapeutic dose by 4 times. The cytochrome P450 isoenzymes CYP2C9 and CYP2C8 and (to a minor extent) CYP3A4 are involved in the O-demethylation of olodaterol, while the uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7 and 1A9 are involved in the formation of olodaterol glucuronides.

Breeding

Tiotropium. The total clearance of tiotropium in healthy volunteers is 880 ml/min. After intravenous administration, tiotropium is mainly excreted unchanged in the urine (74%). After inhalation in COPD patients, urinary excretion at steady state is 18.6% of the dose, the remainder is not absorbed from the intestine and is excreted in the feces. The renal clearance of tiotropium exceeds the glomerular filtration rate, indicating active excretion into the urine. The effective half-life of tiotropium after inhalation in COPD patients ranges 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 intravenous administration of [14C]-labeled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% in the faeces. The amount of unchanged olodaterol recovered in the urine after intravenous administration was 19%. After oral administration, only 9% of the radioactive dose (0.7% unchanged olodaterol) was recovered in the urine, while the majority was recovered in the faeces (84%). More than 90% of the dose was excreted after intravenous administration within 6 days and after oral administration within 5 days. After inhalation, the urinary excretion of unchanged olodaterol during the dosing interval at steady state in healthy volunteers was 5–7% of the dose. Olodaterol plasma concentrations decline in a multiphasic manner after inhalation; the terminal half-life is approximately 45 hours.

Special populations

Olodaterol: A pharmacokinetic meta-analysis using data from 2 controlled clinical trials involving 405 patients with COPD and 296 patients with asthma showed that dose adjustment based on patient age, gender and body weight is not necessary due to the systemic exposure of olodaterol.

Race

Olodaterol: Comparison of pharmacokinetic data obtained in clinical studies revealed a trend towards higher systemic exposure to olodaterol in patients of Japanese ethnicity and other Mongoloid races compared to patients of Caucasian race.

In clinical studies of olodaterol administered at doses exceeding 2 times the recommended therapeutic dose for more than one year, no safety concerns were identified in patients of Caucasian and Mongoloid races.

Kidney failure

Tiotropium: Following once-daily inhalation of tiotropium to steady state in COPD patients with mild renal impairment (CLCR 50–80 mL/min), there was a small increase in AUC0-6,ss (1.8 to 30% increase) and a similar Cmax,ss compared to patients with normal renal function (CLcr > 80 mL/min). In patients with moderate or severe renal impairment (CLCR < 50 mL/min), intravenous administration of tiotropium resulted in a doubling of plasma concentrations (82% increase in AUC0-4h and 52% increase in Cmax) compared to patients with normal renal function, which was consistent with observations after dry powder inhalation.

Olodaterol: No clinically relevant increase in systemic exposure was observed in patients with renal impairment.

Liver failure

Tiotropium: Hepatic impairment has no significant effect on the pharmacokinetics of tiotropium. Tiotropium is excreted primarily by the kidneys (74% in healthy young volunteers) and by simple non-enzymatic ester cleavage to pharmacologically inactive products.

Olodaterol: No differences in olodaterol clearance (and protein binding) have been demonstrated between patients with mild/moderate hepatic impairment and healthy volunteers. No studies have been conducted in patients with severe hepatic impairment.

Indication

SPIOLTO RESPIMAT is indicated as maintenance bronchodilator therapy for the relief of symptoms in adult patients with chronic obstructive pulmonary disease (COPD).

Contraindication

Hypersensitivity to the active substances or to other components of the drug (see section "Composition").

History of hypersensitivity to atropine or its derivatives, such as ipratropium or oxitropium.

Interaction with other medicinal products and other types of interactions

Although no specific in vivo drug interaction studies have been conducted with SPIOLTO RESPIMAT, SPIOLTO RESPIMAT has been used concomitantly with other drugs used in the treatment of COPD, including short-acting sympathomimetic bronchodilators and inhaled corticosteroids, without clinical evidence of drug-drug interactions.

Anticholinergics

The concomitant use of tiotropium bromide, one of the components of SPIOLTO RESPIMAT, with other anticholinergic agents has not been studied and is therefore not recommended.

Adrenergic drugs

Concomitant use of other adrenergic drugs (alone or as part of combination therapy) may enhance the undesirable effects of SPIOLTO RESPIMAT.

Xanthine derivatives, steroids, diuretics

Concomitant use of xanthine derivatives, steroids or diuretics (not belonging to the potassium-sparing group) may enhance the hypokalemic effect of adrenomimetics (see section "Special warnings and precautions for use").

Beta-blockers

Beta-blockers may reduce or antagonize the effect of olodaterol. In this case, cardioselective beta-blockers are preferred, although they should be used with caution.

MAO inhibitors, tricyclic antidepressants and drugs that may prolong the QT interval

Monoamine oxidase inhibitors, tricyclic antidepressants or other drugs that may prolong the QT interval may enhance the effects of SPIOLTO RESPIMAT on the cardiovascular system.

Pharmacokinetic interaction

In interaction studies with the concomitant use of fluconazole, a standard CYP2C9 inhibitor, no relevant effect on the systemic exposure of olodaterol was observed.

Concomitant use of ketoconazole, a potent P-gp and CYP3A4 inhibitor, increased systemic exposure to olodaterol by approximately 70%. No dose adjustment of SPIOLTO RESPIMAT is required.

In vitro studies have shown that olodaterol does not inhibit CYP enzymes or drug transporters at plasma concentrations achieved in clinical practice.

Application features

Asthma

SPIOLTO RESPIMAT should not be used in patients with asthma. The efficacy and safety of SPIOLTO RESPIMAT in asthma have not been studied.

Acute bronchospasm

SPIOLTO RESPIMAT is not intended for the treatment of acute episodes of bronchospasm, i.e. as an emergency aid.

The use of SPIOLTO RESPIMAT, as with other inhaled medicinal products, may lead to paradoxical bronchospasm, which can sometimes be life-threatening. If paradoxical bronchospasm develops, SPIOLTO RESPIMAT should be discontinued immediately and alternative therapy should be instituted.

Anticholinergic effects associated with tiotropium

Angle-closure glaucoma, prostatic hyperplasia, or bladder neck obstruction

Due to the anticholinergic activity of tiotropium, SPIOLTO RESPIMAT should be used with caution in patients with angle-closure glaucoma, prostatic hyperplasia or bladder neck obstruction.

Symptoms from the organs of vision

Patients should be instructed to avoid contact with the eyes as this may precipitate or worsen angle-closure glaucoma, eye pain or discomfort, temporary blurred vision, halos or colored spots before the eyes in combination with redness of the eye in the form of conjunctival hyperemia or corneal edema. If these symptoms occur in any combination, SPIOLTO RESPIMAT should be discontinued immediately and medical attention should be sought immediately.

Dental caries

Dryness of the oral mucosa observed during treatment with anticholinergic agents may be associated with dental caries in the long term.

Patients with renal impairment

Since increased plasma concentrations of tiotropium are observed in patients with moderate or severe renal impairment (creatinine clearance ≤ 50 ml/min), SPIOLTO RESPIMAT should only be used if the expected benefit outweighs the potential risk. There are no data on long-term use in patients with severe renal impairment (see section 5.1).

Cardiovascular effects

Experience with SPIOLTO RESPIMAT in patients with a history of myocardial infarction within the previous year, unstable or life-threatening cardiac arrhythmia, hospitalised for heart failure within the previous year or diagnosed with paroxysmal tachycardia (> 100 beats per minute) is limited as these patients were not included in clinical trials. SPIOLTO RESPIMAT should be used with caution in such patients.

Olodaterol, like other β2-adrenergic agonists, may have clinically significant cardiovascular effects in some patients (increased heart rate, increased blood pressure (BP) and/or symptoms). If such effects occur, treatment may need to be discontinued. In addition, β2-adrenergic agonists have been reported to cause ECG changes such as T wave flattening and ST segment depression, although the clinical significance of these changes is unknown.

Long-acting β2-adrenergic agonists should be used with caution in patients with cardiovascular disease, especially ischemic heart disease, severe heart failure, cardiac arrhythmias, hypertrophic obstructive cardiomyopathy, hypertension and aneurysm, in patients with seizure disorders or thyrotoxicosis, in patients with established or suspected QT prolongation (e.g. QT > 0.44 sec), and in patients with unusual reactions to sympathomimetic amines.

Hypokalemia

β-Adrenergic agonists may cause significant hypokalemia in some patients, which creates the prerequisites for the occurrence of undesirable effects on the cardiovascular system. The decrease in serum potassium is usually short-lived and does not require correction. In patients with severe COPD, hypokalemia may be exacerbated by hypoxia and concomitant therapy (see section "Interaction with other medicinal products and other types of interactions"), which may increase the risk of arrhythmias.

Hyperglycemia

Inhaled use of high doses of β2-adrenomimetics may lead to an increase in blood plasma glucose levels.

Anesthesia

Caution should be exercised in elective surgery with halogenated hydrocarbon anesthetics due to the increased potential for adverse cardiac effects with the use of β-agonist bronchodilators.

SPIOLTO RESPIMAT should not be used in combination with any other medicinal product containing long-acting β2-adrenomimetics.

Patients who frequently use inhaled short-acting β2-adrenergic agonists (e.g. 4 times a day) should be informed that these drugs are used

Specifications
Characteristics
Active ingredient
Tiotropium, Olodaterol
ATC code
R RESPIRATORY SYSTEM AGENTS; R03 DETERGENTS FOR THE TREATMENT OF OBSTRUCTIVE AIRWAY DISEASES; R03A ADRENERGIC INHALED MEDICINES; R03A L Adrenergic agents in combination with anticholinergic agents; R03A L06 Olodaterol and tiotropium bromide
Country of manufacture
Germany
Form
Liquids
Method of application
For administration into the lungs
Producer
Boehringer Ingelheim
Quantity per package
60 doses
Trade name
Spiolto Respimat
Vacation conditions
By prescription
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1 933.25 грн.