What is Yanimo Respimat used for?

Spiolto Respimat is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).

What is the active ingredient in Yanimo Respimat?

Olodaterolum + Tiotropium (Olodateroli hydrochloridum, Tiotropii bromidum monohydricum)

What pharmaceutical form is Yanimo Respimat available in?

Yanimo Respimat: Roztwór do inhalacji 2,5 mikrograma + 2,5 mikrograma (wziewna)

Is Yanimo Respimat OTC or prescription only?

Yanimo Respimat requires a doctor's prescription.

What are the side effects of Yanimo Respimat?

a. Summary of the safety profile Many of the listed undesirable effects can be assigned to the anticholinergic properties of tiotropium bromide or to the ß 2 -adrenergic properties of olodaterol, the components of Spiolto Respimat b. Tabulated summary of adverse reactions The frequencies assigned to the undesirable effects listed below are based on the crude incidence rates of adverse drug reactions (i.e. events attributed to Spiolto Respimat) observed in the tiotropium 5 micro

Who should NOT take Yanimo Respimat?

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. History of hypersensitivity to atropine or its derivatives, e.g. ipratropium or oxitropium.

Does Yanimo Respimat interact with other medications?

Although no formal in vivo drug interaction studies have been performed between Spiolto Respimat and other drugs, inhaled Spiolto Respimat has been used concomitantly with other COPD medicinal products, including short acting sympathomimetic bronchodilators and inhaled corticosteroids without clinical evidence of drug interactions. Anticholinergic agents The co-administration of tiotropium bromide, one component of Spiolto Respimat, with other anticholinergic containing drugs has not been studie

Can Yanimo Respimat be used during pregnancy?

Pregnancy Tiotropium There is a very limited amount of data from the use of tiotropium in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses (see 5.3). Olodaterol For olodaterol no clinical data on exposed pregnancies are available. Preclinical data for olodaterol revealed effects typical for beta-adrenergic agonists at high multiples of the therapeutic doses (see section 5.3). As

What precautions should be taken with Yanimo Respimat?

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Who manufactures Yanimo Respimat?

Boehringer Ingelheim International GmbH (Hiszpania)

What ATC class does Yanimo Respimat belong to?

Yanimo Respimat: ATC R03AL06. ATC is the WHO Anatomical Therapeutic Chemical classification — it groups drugs by organ system and pharmacological mechanism.

Yanimo Respimat

This information is for educational purposes only. It is not intended as medical advice. Always consult a qualified healthcare professional.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with anticholinergics ATC code: R03AL06 Mechanism of action Spiolto Respimat Spiolto Respimat is a fixed dose combination inhalation solution containing a long acting muscarinic receptor antagonist, tiotropium and a long acting beta2-adrenergic agonist, olodaterol (LAMA/LABA) which is delivered via the Spiolto Respimat soft mist inhaler device. The two active ingredients provide additive bronchodilation due to their different mode of action.‍‍‍‍‍‍‍‍‍‍‍‍‍ Since muscarinic receptors appear to be more prominent in the central airways while ß 2 adrenoceptors have a higher expression level in the peripheral airways, a combination of tiotropium and olodaterol should provide optimal bronchodilatation in all regions of the lungs. Tiotropium Tiotropium bromide is a long-acting, specific antagonist at muscarinic receptors. It has similar affinity to the subtypes, M 1 to M 5 . In the airways, tiotropium bromide competitively and reversibly binds to the M 3 receptors in the bronchial smooth musculature, antagonising the cholinergic (bronchoconstrictive) effects of acetylcholine, resulting in bronchial smooth muscle relaxation. The effect was dose dependent and lasted longer than 24h. As an N-quaternary anticholinergic, tiotropium bromide is topically (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic range before systemic anticholinergic effects may occur. Olodaterol Olodaterol has a high affinity and high selectivity to the human beta 2 -adrenoceptor. In vitro studies have shown that olodaterol has 241-fold greater agonist activity at beta 2 -adrenoceptors compared to beta 1 -adrenoceptors and 2299-fold greater agonist activity compared to beta 3 -adrenoceptors. The compound exerts its pharmacological effects by binding and activation of beta 2 -adrenoceptors after topical administration by inhalation. Activation of these receptors in the airways results in a stimulation of intracellular adenyl cyclase, an enzyme that mediates the synthesis of cyclic-3',5' adenosine monophosphate (cAMP). Elevated levels of cAMP induce bronchodilation by relaxation of airway smooth muscle cells. Olodaterol has the pre-clinical profile of a long-acting selective beta 2 -adrenoceptor agonist (LABA) with a fast onset of action and a duration of action of at least 24 hours. Beta-adrenoceptors are divided into three subtypes, beta 1 -adrenoceptors predominantly expressed on cardiac muscle, beta 2 -adrenoceptors predominantly expressed on airway smooth muscle and beta 3 -adrenoceptors predominantly expressed on adipose tissue. Beta 2 -agonists cause bronchodilation. Although the beta 2 -adrenoceptor is the predominant adrenergic receptor in the airway smooth muscle it is also present on the surface of a variety of other cells, including lung epithelial and endothelial cells and in the heart. The precise function of beta 2 -receptors in the heart is not known, but their presence raises the possibility that even highly selective beta 2 -adrenergic agonists may have cardiac effects. Effects on cardiac electrophysiology Tiotropium In a dedicated QT study involving 53 healthy volunteers, tiotropium inhalation powder 18 microgram and 54 microgram (i.e. three times the therapeutic dose) over 12 days did not significantly prolong QT intervals of the ECG. Olodaterol The effect of olodaterol on the QT/QTc interval of the ECG was investigated in 24 healthy male and female volunteers in a double-blind, randomised, placebo- and active (moxifloxacin) controlled study. Olodaterol at single doses of 10, 20, 30 and 50 microgram, demonstrated that compared with placebo, the mean changes from baseline in QT interval over 20 minutes to 2 hours after dosing increased dose-dependently from 1.6 (10 microgram olodaterol) to 6.5 ms (50 microgram olodaterol), with the upper limit of the two-sided 90% confidence intervals being less than 10 ms at all dose levels for individually corrected QT (QTcI). The effect of 5 microgram and 10 microgram olodaterol on heart rate and rhythm was assessed using continuous 24-hour ECG recording (Holter monitoring) in a subset of 772 patients in the 48-week, placebo-controlled Phase 3 trials. There were no dose- or time-related trends or patterns observed for the magnitudes of mean changes in heart rate or premature beats. Shifts from baseline to the end of treatment in premature beats did not indicate meaningful differences between olodaterol 5 microgram, 10 microgram and placebo. Spiolto Respimat Two 52-week randomized, double-blind trials using Spiolto Respimat enrolled 5162 patients with COPD. In a pooled analysis the number of subjects with changes from baseline-corrected QTcF (Fridericia correction) interval of >30 msec at 40 minutes post-dose on day 85, 169, and 365, ranged from 3.1%, 4.7%, and 3.6% for the Spiolto Respimat group compared to 4.1%, 4.4%, and 3.6% for olodaterol 5 microgram and 3.4%, 2.3%, and 4.6% for the tiotropium 5 microgram group, respectively. Clinical efficacy and safety The Phase III clinical development program for Spiolto Respimat included three randomised, double-blind trials: (i) two replicate, 52 week parallel group trials comparing Spiolto Respimat with tiotropium 5 microgram and olodaterol 5 microgram (1029 received Spiolto Respimat) [Trials 1 and 2] (ii) one 6 week cross-over trial comparing Spiolto Respimat with tiotropium 5 microgram and olodaterol 5 microgram and placebo (139 received Spiolto Respimat) [Trial 3] In these trials, the comparator products, tiotropium 5 microgram, olodaterol 5 microgram and placebo were administered via the Respimat inhaler. Patient characteristics The majority of the 5162 patients recruited in the global, 52 week trials [Trials 1 and 2] were male (73%), white (71%) or Asian (25%), with a mean age of 64.0 years. Mean post-bronchodilator FEV 1 was 1.37 L (GOLD 2 [50%], GOLD 3 [39%], GOLD 4 [11%]). Mean β 2 -agonist responsiveness was 16.6% of baseline (0.171 L). Pulmonary medications allowed as concomitant therapy included inhaled steroids [47%] and xanthines [10%]. The 6 week trial [Trial 3] was conducted in Europe and North America. The majority of the 219 recruited patients were male (59%) and white (99%), with a mean age of 61.1 years. Mean post-bronchodilator FEV 1 was 1.55 L (GOLD 2 [64%], GOLD 3 [34%], GOLD 4 [2%]). Mean β 2 -agonist responsiveness was 15.9% of baseline (0.193 L). Pulmonary medications allowed as concomitant therapy included inhaled steroids [41%] and xanthines [4%]. Effects on lung function In the 52 week trials, Spiolto Respimat administered once daily in the morning, provided clear improvement in lung function within 5 minutes after the first dose compared to tiotropium 5 microgram (mean increase in FEV 1 of 0.137 L for Spiolto Respimat vs. 0.058 L for tiotropium 5 microgram [p<0.0001] and 0.125 L for olodaterol 5 microgram [p=0.16]). In both studies, significant improvements were observed in FEV 1 AUC 0-3h response and trough FEV 1 response after 24 weeks (lung function primary endpoints) for Spiolto Respimat compared to tiotropium 5 microgram and olodaterol 5 microgram (Table 1). Table 1 Difference in FEV 1 AUC 0-3h and trough FEV 1 response for Spiolto Respimat compared to tiotropium 5 microgram, olodaterol 5 microgram after 24 weeks (Trials 1 and 2) FEV 1 AUC 0-3h response Trough FEV 1 response Trial 1 Trial 2 Trial 1 Trial 2 n Mean n Mean n Mean n Mean Spiolto Respimat versus 522 -- 502 -- 521 -- 497 -- Tiotropium 5 microgram 526 0.117 L 500 0.103 L 520 0.071 L 498 0.050 L Olodaterol 5 microgram 525 0.123 L 507 0.132 L 519 0.082 L 503 0.088 L pre-treatment baseline FEV 1 : Trial 1 = 1.16 L; Trial 2 = 1.15 L p≤0.0001 for all comparisons n= number of patients Patients with a higher degree of reversibility at baseline generally exhibited a higher bronchodilator response with Spiolto Respimat than patients with a lower degree of reversibility at baseline. The increased bronchodilator effects of Spiolto Respimat compared to tiotropium 5 microgram and olodaterol 5 microgram were maintained throughout the 52 week treatment period. Spiolto Respimat also improved morning and evening PEFR (peak expiratory flow rate) compared to tiotropium 5 microgram and olodaterol 5 microgram as measured by patient's daily recordings. In the 6 week trial, Spiolto Respimat showed a significantly greater FEV 1 response compared to tiotropium 5 microgram, olodaterol 5 microgram and placebo (p<0.0001) over the full 24 hour dosing interval (Table 2). Table 2 Average difference in FEV1 (L) over 3 hr, 12 hr and 24 hr and difference in trough FEV1 (L) for Spiolto Respimat compared to tiotropium 5 microgram, olodaterol 5 microgram and placebo after 6 weeks (Trial 3) n 3 hr average n 12 hr average 24 hr average 1 Trough Spiolto Respimat versus 138 138 Tiotropium 5 microgram 137 0.109 135 0.119 0.110 0.079 Olodaterol 5 microgram 138 0.109 136 0.126 0.115 0.092 Placebo 135 0.325 132 0.319 0.280 0.207 pre-treatment baseline FEV 1 = 1.30 L 1 primary endpoint p<0.0001 for all comparisons n= number of patients Dyspnea After 24 weeks (Trials 1 and 2), mean TDI focal score was 1.98 units for Spiolto Respimat, with a significant improvement compared to tiotropium 5 microgram (mean difference 0.36, p=0.008) and olodaterol 5 microgram (mean difference 0.42 (p=0.002). More patients treated with Spiolto Respimat had a clinically meaningful improvement in TDI focal score (MCID, defined as a value of at least 1 unit) compared to tiotropium 5 microgram (54.9% vs. 50.6%, p=0.0546) and olodaterol 5 microgram (54.9% vs. 48.2%, p=0.0026). Rescue Medication Use Patients treated with Spiolto Respimat used less daytime and nighttime rescue salbutamol compared to patients treated with tiotropium 5 microgram and olodaterol 5 microgram (mean daytime rescue use for Spiolto Respimat of 0.76 occasions per day compared to 0.97 occasions per day for tiotropium 5 microgram and 0.87 occasions per day for olodaterol 5 microgram, p<0.0001; mean nighttime rescue use for Spiolto Respimat of 1.24 occasions per day compared to 1.69 occasions per day for tiotropium 5 microgram and 1.52 occasions per day for olodaterol 5 microgram, p<0.0001, Trials 1 and 2). Patient Global Rating Patients treated with Spiolto Respimat perceived a greater improvement in their respiratory condition compared to tiotropium 5 microgram and olodaterol 5 microgram, as measured by a Patient´s Global Rating (PGR) scale (Trials 1 and 2). Exacerbations Tiotropium 5 microgram has previously demonstrated a statistically significant reduction in risk of a COPD exacerbation compared to placebo. COPD exacerbations was included as an additional endpoint in the 52 week pivotal trials (Trials 1 and 2). In the combined dataset, the proportion of patients experiencing at least one moderate/severe COPD exacerbation was 27.7% for Spiolto Respimat and 28.8% for tiotropium 5 microgram (p=0.39). These studies were not specifically designed to evaluate the effect of treatments on COPD exacerbations. In a one-year, randomised, double-blind, active-controlled parallel group clinical trial (Trial 9) Spiolto Respimat was compared with tiotropium 5 microgram on COPD exacerbations. All respiratory medications except anticholinergics, long-acting beta-agonists and combinations thereof were allowed as concomitant treatment, i.e. rapidly acting beta-agonists, inhaled corticosteroids and xanthines. The primary endpoint was the annualised rate of moderate to severe COPD exacerbations (3939 patients received Spiolto Respimat and 3941 patients received tiotropium 5 microgram). The majority of patients were male (71.4%) and Caucasian (79.3%). The mean age was 66.4 years, mean post-bronchodilator FEV1 was 1.187 L (SD 0.381), and 29.4% of patients had a history of clinically important cardiovascular disease. Moderate-to-severe exacerbations of COPD were defined as “a complex of lower respiratory events/symptoms (increase or new onset) related to the underlying COPD, with duration of three days or more, requiring a prescription of antibiotics and/or systemic steroids and/or hospitalisation”. Spiolto Respimat treatment resulted in a 7% reduction in the annualised rate of moderate to severe COPD exacerbation in comparison to tiotropium 5 microgram (rate ratio (RR) 0.93, 99% Confidence Interval (CI), 0.85-1.02, p=0.0498). The study did not reach p<0.01, the pre-specified significance level of the study. Health-related Quality of Life Spiolto Respimat showed improvement in health-related quality of life as indicated by a reduction in St. George Respiratory Questionnaire (SGRQ) total score. After 24 weeks (Trials 1 and 2), there was a statistically significant improvement in mean SGRQ total score for Spiolto Respimat compared to tiotropium 5 microgram and olodaterol 5 microgram (Table 3); improvements were seen in all SGRQ domains. More patients treated with Spiolto Respimat had a clinically meaningful improvement in SGRQ total score (MCID, defined as a decrease of at least 4 units from baseline) compared to tiotropium 5 microgram (57.5% vs. 48.7%, p=0.0001) and olodaterol 5 microgram (57.5% vs. 44.8%, p<0.0001). Table 3: SGRQ total score after 24 weeks of treatment (Trials 1 and 2) n Treatment Mean (change from baseline) Difference to Spiolto Respimat Mean (p-value) Total score Baseline 43.5 Spiolto Respimat 979 36.7 (-6.8) Tiotropium 5 microgram 954 37.9 (-5.6) -1.23 (p=0.025) Olodaterol 5 microgram 954 38.4 (-5.1) -1.69 (p=0.002) n= number of patients In two additional 12-week, placebo-controlled clinical trials (Trials 7 and 8), SGRQ total score at 12 weeks was also included as primary endpoint as a measure of health-related quality of life. In the 12-week trials, Spiolto Respimat demonstrated an improvement compared with placebo at week 12 in mean SGRQ total 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 trials, the proportion of patients with a clinically meaningful decrease in SGRQ total score (defined as a decrease of at least 4 units from baseline) at week 12 was greater for Spiolto Respimat (52% [206/393]) compared with tiotropium 5 microgram (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, breathing discomfort and exercise endurance The effect of Spiolto Respimat on inspiratory capacity, breathing discomfort and symptom-limited exercise endurance was investigated in three randomised, double-blind trials in COPD patients: (i) two replicate, 6 week cross-over trials comparing Spiolto Respimat with tiotropium 5 microgram, olodaterol 5 microgram and placebo during constant work rate cycling (450 received Spiolto Respimat) [Trials 4 and 5] (ii) one 12 week parallel group trial comparing Spiolto Respimat with placebo during constant work rate cycling (139 received Spiolto Respimat) and constant speed walking (sub-set of patients) [Trial 6] Spiolto Respimat significantly improved inspiratory capacity at rest two hours post-dose compared to tiotropium 5 microgram (0.114 L, p<0.0001; Trial 4, 0.088 L, p=0.0005; Trial 5), olodaterol 5 microgram (0.119 L, p<0.0001; Trial 4, 0.080 L, p=0.0015; Trial 5) and placebo (0.244 L, p<0.0001; Trial 4, 0.265 L, p<0.0001; Trial 5) after 6 weeks. In Trials 4 and 5, Spiolto Respimat significantly improved endurance time during constant work rate cycling compared to placebo after 6 weeks (Trial 4: geometric mean endurance time of 454 s for Spiolto Respimat compared to 375 seconds for placebo (20.9% improvement, p<0.0001); Trial 5: geometric mean endurance time of 466 seconds for Spiolto Respimat compared to 411 seconds for placebo (13.4% improvement, p<0.0001). In Trial 6, Spiolto Respimat significantly improved endurance time during constant work rate cycling compared to placebo after 12 weeks (geometric endurance time of 528 seconds for Spiolto Respimat compared to 464 seconds for placebo (13.8% improvement, p=0.021). Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Spiolto Respimat in all subsets of the paediatric population in chronic obstructive pulmonary disease (COPD) as per decision on class waivers (see section 4.2 for information on paediatric use).

Yanimo Respimat

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