Spiolto Respimat

Tiotropium, olodaterol.

The SPIOLTO RESPIMAT is a soft mist inhaler delivering tiotropium + olodaterol inhalation solution.
The delivered dose is 2.5 microgram tiotropium and 2.5 microgram olodaterol per puff (2 puffs comprise one medicinal dose) and is equivalent to 3.124 microgram tiotropium bromide monohydrate and 2.7 microgram olodaterol hydrochloride.
The delivered dose is the dose which is available for the patient after passing the mouthpiece.
Excipients/Inactive Ingredients: Benzalkonium chloride, disodium edetate, water, purified, 1 M hydrochloric acid (for pH adjustment).

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with anticholinergics. ATC code: RO3AL06.
Pharmacology: Pharmacodynamics: Mode of action: Tiotropium, a long acting muscarinic antagonist and olodaterol a long acting beta₂-adrenergic are administered together in the SPIOLTO RESPIMAT soft mist inhaler. These two active ingredients provide additive bronchodilation due to their different mode of action and different locations of the target receptors in the airways.
Tiotropium: Tiotropium bromide is a long-acting, muscarinic receptor antagonist (LAMA), in clinical medicine often called an anticholinergic. It has a similar affinity to the subtypes of muscarinic receptors M₁ to M₅. In the airways, inhibition of M₃-receptors at the smooth muscle results in relaxation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In pre-clinical in vitro as well as in vivo studies bronchoprotective effects were dose-dependent and lasted longer than 24 hours. The long duration of the effect is likely to be due to its very slow dissociation from M₃-receptors, exhibiting a significantly longer dissociation half-life than that seen with ipratropium. As an N-quaternary anticholinergic tiotropium is topically (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic range before giving rise to systemic anti-cholinergic effects.
Dissociation from M₂-receptors is faster than from M₃, which in functional in vitro studies, elicited (kinetically controlled) receptor subtype selectivity of M₃ over M₂.
The high potency and slow receptor dissociation found its clinical correlate in significant and long-acting bronchodilation in patients with COPD.
The bronchodilation following inhalation of tiotropium is primarily a local effect (on the airways) not a systemic one.
Olodaterol: Olodaterol has a high affinity and high selectivity to the human beta₂-adrenoceptor. In vitro studies have shown that olodaterol has 241-fold greater agonist activity at beta₂- adrenoceptors compared to beta₁-adrenoceptors and 2299-fold greater agonist activity compared to beta₃-adrenoceptors. The compound exerts its pharmacological effects by binding and activation of beta₂-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 beta₂-adrenoceptor agonist (LABA) with a fast onset of action and duration of action of at least 24 hours.
Beta-adrenoceptors are divided into three subtypes, beta₁-adrenoceptors predominantly expressed on cardiac muscle, beta₂-adrenoceptors predominantly expressed on airway smooth muscle and beta₃-adrenoceptors predominantly expressed on adipose tissue. Beta₂-agonists cause bronchodilation. Although the beta₂-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 beta₂-receptors in the heart is not known, but their presence raises the possibility that even highly selective beta₂-adrenergic agonists may have cardiac effects.
Clinical Trials: 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.
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: In two 52-week randomized, double-blind trials using SPIOLTO RESPIMAT that enrolled 5162 patients with COPD, ECG assessments were performed post-dose on days 1, 85, 169, and 365. In a pooled analysis the number of subjects with changes from baseline-corrected QT interval of >30 msec using both the Bazett (QTcB) and Fredericia (QTcF), corrections of QT for heart rate ranged from 4.9-6.4% (QTcB) and 1.3-4.7% (QTcF) for the SPIOLTO RESPIMAT group compared to 5.0-6.0% (QTcB) and 1.3-4.4% (QTcF) for olodaterol 5 microgram and 5.3-6.5% (QTcB) and 2.1-4.6% (QTcF) for tiotropium 5 microgram across the assessments conducted.
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.
All studies included lung function measurements (forced expiratory volume in one second, FEV₁). In the 52 week studies, lung function was measured up to 3 hrs post-dose (12 hrs post- dose in a sub-set of patients) and at 23-24 hrs post-dose; the primary lung function efficacy endpoints were change from pre-treatment baseline (response) in FEV₁ AUC_0-3h and trough FEV₁ after 24 weeks. In the 6 week study, lung function was measured up to 12 hrs post-dose and at 22-24 hrs post-dose; the primary efficacy endpoint was FEV₁ AUC_0-24h response after 6 weeks. The 52 week trials also included the St. George's Respiratory Questionnaire (SGRQ) as a primary endpoint as a measure of health-related quality of life and the Mahler Transition Dyspnoea Index (TDI) as a key secondary endpoint as a measure of dyspnoea.
Patients enrolled into the Phase III program were 40 years of age or older with a clinical diagnosis of COPD, had a smoking history of more than 10 pack years and had moderate to very severe pulmonary impairment (post-bronchodilator FEV₁ less than 80% predicted normal (GOLD Stage 2-4); post-bronchodilator FEV₁ to FVC ratio of less than 70%).
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 FEV₁ was 1.37 L (GOLD 2 [50%], GOLD 3 [39%], and GOLD 4 [11%]). Mean β₂-agonist responsiveness was 16.6% of baseline (0.171 L). Pulmonary medications allowed as concomitant therapy included inhaled steroids [47%] and xanthine's [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 FEV₁ was 1.55 L (GOLD 2 [64%], GOLD 3 [34%], GOLD 4 [2%]). Mean β₂-agonist responsiveness was 15.9% of baseline (0.193 L). Pulmonary medications allowed as concomitant therapy included inhaled steroids [41%] and xanthines [4%].
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 FEV₁ 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 FEV₁ AUC_0-3h response and trough FEV₁ response after 24 weeks (lung function primary endpoints) for SPIOLTO RESPIMAT compared to tiotropium 5 microgram and olodaterol 5 microgram (see Table 1).


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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 sub-set of patients who completed extended lung function measurements up to 12 hrs post-dose, SPIOLTO RESPIMAT showed a significantly greater FEV₁ response compared to tiotropium 5 microgram and olodaterol 5 microgram over the full 24 hour dosing interval (see Figure 1 and Table 2).


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In the 6 week trial, SPIOLTO RESPIMAT showed a significantly greater FEV₁ response compared to tiotropium 5 microgram, olodaterol 5 microgram and placebo over the full 24 hour dosing interval (see Figure 2 and Table 3).


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Health-related Quality of Life: After 24 weeks, SPIOLTO RESPIMAT significantly improved mean SGRQ total score compared to tiotropium 5 microgram and olodaterol 5 microgram (Table 4); 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). (See Table 4).


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In two additional 12-week, placebo-controlled clinical trials, SGRQ total score at 12 weeks was also included as primary endpoint as a measure of healthy-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 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%) compared with tiotropium 5 microgram (41%; odds ratio: 1.56 (95% CI: 1.17, 2.07), p=0.0022) and placebo (32%; odds ratio: 2.35 (95% CI: 1.75, 3.16), p <0.0001).
Dyspnoea: After 24 weeks, SPIOLTO RESPIMAT significantly improved mean TDI focal score compared to tiotropium 5 microgram and olodaterol 5 microgram (Table 5). 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). (See Table 5).


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Rescue Medication Use: Patients treated with SPIOLTO RESPIMAT used less daytime and night-time rescue salbutamol compared to patients treated with tiotropium 5 microgram and olodaterol 5 microgram.
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.
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 a 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.
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 compared to tiotropium 5 microgram, olodaterol 5 microgram and placebo after 6 weeks (Trials 4 and 5; Table 6) and compared to placebo after 12 weeks (0.234 L, p<0.0001; 95% CI: 0.133, 0.336; Trial 6). (See Table 6).


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In Trials 4 and 5, SPIOLTO RESPIMAT improved endurance time during constant work rate cycling by 20.9% and 13.4% compared to placebo (Table 7). In Trial 6, SPIOLTO RESPIMAT improved endurance time during constant work rate cycling by 12.6% after the first dose (in a sub-set of patients), by 22.9% after 6 weeks and by 13.8% after 12 weeks compared to placebo. The endurance time during constant speed walking (in a sub-set of patients) increased by 20.6% after 6 weeks and by 20.9% after 12 weeks compared to placebo although the result was not statistically significant (Table 8).


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In Trials 4 and 5, SPIOLTO RESPIMAT decreased the slope of breathing discomfort during constant work rate cycling compared to placebo (nominal p<0.0005; Table 9). (See Table 9).


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Pharmacokinetics: When tiotropium and olodaterol were administered in combination by the inhaled route, the pharmacokinetic parameters for each component were similar to those observed when each active substance was administered separately.
Tiotropium and olodaterol demonstrate linear pharmacokinetics in the therapeutic range. On repeated once-daily inhalation administration, steady state of tiotropium is reached by day 7. Steady state of olodaterol is achieved after 8 days of once-daily inhalation, and accumulation is up to 1.8-fold as compared to a single dose.
Absorption: Tiotropium: Urinary excretion data from young healthy volunteers suggests that approximately 33% of the dose inhaled via the RESPIMAT inhaler reaches the systemic circulation. The absolute bioavailability from an orally administered solution was found to be 2-3%. Maximum tiotropium plasma concentrations are observed 5-7 minutes after the inhalation via RESPIMAT.
Olodaterol: In healthy volunteers the absolute bioavailability of olodaterol following inhalation was estimated to be approximately 30%, whereas the absolute bioavailability was below 1% when given as an oral solution. Maximum olodaterol plasma concentrations generally are reached within 10 to 20 minutes following drug inhalation via RESPIMAT.
Distribution: Tiotropium has a plasma protein binding of 72% and shows a volume of distribution of 32 L/kg. Studies in rats have shown that tiotropium does not penetrate the blood-brain barrier to any relevant extent.
Olodaterol has a plasma protein binding of approximately 60% and shows a volume of distribution of 1110 L.
Biotransformation: Tiotropium: The extent of metabolism is small. This is evident from 74% of an intravenous dose being excreted in the urine as unchanged drug. The ester tiotropium is nonenzymatically cleaved into its alcohol and acid component (N-methylscopine and dithienylglycolic acid, respectively), both not binding to muscarinic receptors. In vitro experiments with human liver microsomes and human hepatocytes suggest that some further drug (<20% of the dose after intravenous administration) is metabolized by cytochrome P450 (CYP) 2D6 and 3A4 dependent oxidation and subsequent glutathione conjugation to a variety of Phase II-metabolites.
Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. Of the six metabolites identified, only the unconjugated demethylation product (SOM 1522) binds to β₂-receptors; this metabolite however is not detectable in plasma after chronic inhalation of the recommended therapeutic dose or doses of up to 4-fold higher. Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7 and 1A9 were shown to be involved in the formation of olodaterol glucuronides.
Elimination: Tiotropium: Intravenously administered tiotropium is mainly excreted unchanged in urine (74%). The total clearance in healthy volunteers is 880 mL/min. After inhalation by COPD patients to steady-state, urinary excretion is 18.6% of the dose, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces. The renal clearance of tiotropium exceeds the glomerular filtration rate, indicating active secretion into the urine. The effective half-life of tiotropium following inhalation by COPD patients ranges between 27 and 45 h.
Olodaterol: Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 mL/min. The terminal half-life following intravenous administration is 22 hrs. The terminal half-life following inhalation in contrast is about 45 hrs, indicating that the latter is determined by absorption rather than by elimination processes.
Following intravenous administration of [¹⁴C]-labelled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in feces. The amount of unchanged olodaterol recovered in the urine after intravenous administration was 19%. Following oral administration, only 9% of the radioactivity was recovered in urine, while the major portion was recovered in feces (84%). More than 90% of the dose was excreted within 6 and 5 days following intravenous and oral administration, respectively. Following inhalation, excretion of unchanged olodaterol in urine within the dosing interval in healthy volunteers at steady state accounted for 5-7% of the dose.
Characteristics in Patients: Tiotropium: As expected for all predominantly renally excreted drugs, advancing age was associated with a decrease of tiotropium renal clearance from 347 mL/min in COPD patients <65 years to 275 mL/min in COPD patients ≥65 years. This did not result in a corresponding increase in AUC_0-6,ss or C_max,ss values.
Olodaterol: A pharmacokinetic meta-analysis utilizing data from 2 controlled clinical trials that included 405 patients with COPD and 296 patients with asthma showed that no dose adjustment is necessary due to effects of age, gender and weight on systemic exposure to olodaterol.
Comparison of pharmacokinetic data within and across studies with olodaterol revealed a trend for higher systemic exposure in Japanese and other Asians than in Caucasians.
No safety concerns were identified in clinical studies with olodaterol in Caucasians and Asians of up to one year with olodaterol doses up to twice the recommended therapeutic dose.
Renal Insufficiency: Tiotropium: Following once daily inhaled administration of tiotropium to steady-state in COPD patients with mild renal impairment (CL_CR 50-80 mL/min) resulted in slightly higher AUC_0-6,ss (between 1.8 to 30% higher) and similar C_max,ss compared to patients with normal renal function (CLcr >80 mL/min). In subjects with moderate to severe renal impairment (CL_CR <50 ml/min) intravenous administration of tiotropium resulted in twofold higher total exposure (82% higher AUC_0-4h and 52% higher C_max) compared to subjects with normal renal function, which was confirmed by observations after dry powder inhalation.
Olodaterol: In subjects with severe renal impairment (CL_CR <30 mL/min) systemic exposure to olodaterol was on average 1.4-fold increased. This magnitude of exposure increase does not raise any safety concerns given the safety experience of treatment with olodaterol in clinical studies of up to one year at doses up to twice the recommended therapeutic dose.
Hepatic Insufficiency: Tiotropium: Liver insufficiency is not expected to have any relevant influence on tiotropium pharmacokinetics. Tiotropium is predominantly cleared by renal elimination (74% in young healthy volunteers) and simple non-enzymatic ester cleavage to pharmacologically inactive products.
Olodaterol: In subjects with mild and moderate hepatic impairment systemic exposure to olodaterol was not affected. The effect of severe hepatic impairment on systemic exposure to olodaterol was not investigated.
Drug-Drug Interactions: Pharmacokinetic drug interaction studies with SPIOLTO RESPIMAT have not been performed; however such studies have been conducted with individual components tiotropium and olodaterol.
When tiotropium and olodaterol were administered in combination by the inhaled route, the pharmacokinetic parameters for each component were similar to those observed when each active substance was administered separately.
Tiotropium: An interaction study with tiotropium (14.4 mcg intravenous infusion over 15 minutes) and cimetidine 400 mg three times daily or ranitidine 300 mg once-daily was conducted. Concomitant administration of cimetidine with tiotropium resulted in a 20% increase in the AUC_0-4h, a 28% decrease in the renal clearance of tiotropium and no significant change in the C_max and amount excreted in urine over 96 hours. Co-administration of tiotropium with ranitidine did not affect the pharmacokinetics of tiotropium.
Common concomitant medications (long-acting beta₂-adrenergic agonists (LABA), inhaled corticosterioids (ICS)) used by patients with COPD were not found to alter the exposure to tiotropium.
Olodaterol: Drug-drug interaction studies were carried out using fluconazole as model inhibitor of CYP 2C9 and ketoconazole as potent P-gp and CYP inhibitor.
Fluconazole: Co-administration of 400 mg fluconazole once daily for 14 days had no relevant effect on systemic exposure to olodaterol.
Ketoconazole: Co-administration of 400 mg ketoconazole once daily for 14 days increased olodaterol C_max by 66% and AUC_0-1 by 68%.
Tiotropium: Co-administration of tiotropium bromide, delivered as a fixed-dose combination with olodaterol, for 21 days had no relevant effect on systemic exposure to olodaterol, and vice versa.
Toxicology: Tiotropium + Olodaterol: Single-dose toxicity: For the combination tiotropium + olodaterol single-dose toxicity studies after inhalation administration have been performed for three dose ratios in mice and rats, revealing a low acute toxicity. In mice, the approximate lethal doses (ALD) were 34.8+36.6 mg/kg for tiotropium+olodaterol in the ratio 1:1. In rats, no deaths occurred, therefore the ALDs were >17.9+18.8 mg/kg for tiotropium/olodaterol in the ratio 1:1.
Repeat-dose toxicity: Inhalation repeat-dose toxicity studies for the combination tiotropium+olodaterol were performed in rats (4 weeks) and dogs (up to 13 weeks) at different dose ratios. In the 13-week studies in dogs, body weight development, clinical signs, changes of the cardiovascular system and of respective enzyme activities as well as the macroscopical and microscopical pathology were characteristic β₂-agonistic and anticholinergic effects. In the 13-week toxicity studies with the dose ratio 1:1 for tiotropium/olodaterol, the no observed adverse effect levels (noael) were 14+16 microgram/kg/day.
Reproduction toxicity: No reproduction toxicity studies for the combination were performed.
Tiotropium: In the reproduction studies in rabbits and rats harmful effects with respect to pregnancy, embryo/fetal development, parturition or postnatal development could only be demonstrated at maternally toxic dose levels. In a general reproduction and fertility study in rats, there was no indication of any adverse effect on fertility or mating performance of either treated parents or their offspring at any dosage.
Olodaterol: In rats, no teratogenic effects occurred after inhalation at doses 1054 microgram/kg/day (>2600 times the human exposure (AUC_(0-24h)) at the dose of 5 microgram). In pregnant NZW rabbits, an inhalation dose of 2489 microgram/kg/day (approximately 7130 times the human exposure at 5 microgram based on AUC_(0-24h)) of olodaterol exhibited fetal toxicity characteristically resulting from β-adrenoceptor stimulation; these included patchy ossifications, short/bent bones, partially open eye, cleft palate, cardiovascular abnormalities. No significant effects occurred at a dose of 974 microgram/kg (approximately 1353 times the 5 microgram dose based on AUC_(0-24h)). No impairment of male or female fertility or early embryonic development was seen in the rat up to inhalation doses of 3068 microgram/kg (approximately 2332 times the 5 microgram dose based on AUC_(0-24h)).
No effects were observed on mating, fertility or bearing of live implants to Day 14/15/16 of gestation in the F1 animals in the rat up to inhalation doses of 3665 microgram/kg/day (approximately 2332 times the 5 microgram dose based on AUC_(0-24h)).
Genotoxicity: In vitro mutagenicity for tiotropium or olodaterol alone, did not show any genotoxic potential. In the in vivo rat bone marrow micronucleus assay, after inhalation at dose levels of up to 2266+2174 microgram/kg/day tiotropium+olodaterol for 4 weeks (dose ratio 1:1), the combination was free of genotoxic potential.
In the in vivo rat bone marrow micronucleus assay after inhalation exposure (up to approximately 1092 times the 5 microgram dose based on AUC_(0-24h)) and the in vitro (Ames test, mouse lymphoma assay) mutagenicity assays, olodaterol was free of any genotoxic potential up to very high dose levels. An increased frequency of micronuclei was observed in rats after i.v. exposure at doses of at least 5500-times the 5 microgram dose based on AUC_(0-24h) may be related to drug enhanced (compensatory) erythropoiesis.
Carcinogenicity: No carcinogenicity studies for the combination were performed.
Tiotropium: Tiotropium did not show any carcinogenic potential in the respective studies in mice and rats.
Olodaterol: Lifetime treatment of rats induced class- and rodent-specific leiomyomas of the mesovarium at exposures approximately 2235-fold and 715-fold the exposure at the dose of 5 microgram dose (on systemic exposure). Lifetime treatment of mice induced class- and rodent-specific smooth muscle tumours (leiomyomas, leiomyosarcomas) of the uterus and incidences of sex cord stromal focal hyperplasia and luteal focal hyperplasia in the ovary at exposures approximately 477- to 3596-fold the exposure at the dose of 5 microgram dose (on systemic exposure), again considered as class- and rodent specific (exposure multiples). Both studies revealed no evidence for an olodaterol-related human risk with regard to carcinogenicity or chronic toxicity.

SPIOLTO RESPIMAT is indicated for the second line treatment in patients with COPD when tiotropium or olodaterol alone does not provide adequate responses to reduce airflow obstruction, to improve quality of life and to reduce associated dyspnoea.

The medicinal product is intended for inhalation use only. The cartridge can only be inserted and used in the Respimat inhaler.
Two puffs from the Respimat inhaler comprise one medicinal dose.
Adults: The recommended dose is 5 microgram tiotropium and 5 microgram olodaterol given as two puffs from the Respimat inhaler once daily, at the same time of the day (see Instructions for Use under Cautions for Usage).
The recommended dose should not be exceeded.
Elderly population: Elderly patients can use SPIOLTO RESPIMAT at the recommended dose.
Hepatic impairment and renal impairment: SPIOLTO RESPIMAT contains tiotropium which is a predominantly renally excreted drug and olodaterol, which is predominantly metabolized in the liver.
Hepatic impairment: Patients with mild and moderate hepatic impairment can use SPIOLTO RESPIMAT at the recommended dose.
There are no data available for use of olodaterol in patients with severe hepatic impairment.
Renal impairment: Renally impaired patients can use SPIOLTO RESPIMAT at the recommended dose.
SPIOLTO RESPIMAT contains tiotropium, which is a predominantly renally excreted drug. Therefore, SPIOLTO RESPIMAT use should be monitored closely in patients with moderate to severe renal impairment (creatinine clearance ≤50 ml/min).
SPIOLTO RESPIMAT contains olodaterol. There is limited experience with the use of olodaterol in patients with severe renal impairment.
Paediatric population: There is no relevant use of SPIOLTO RESPIMAT in the paediatric population (under 18 years) in COPD. The safety and effectiveness of SPIOLTO RESPIMAT in the paediatric population have not been established.
Method of administration: To ensure proper administration of the medicinal product, the patient should be shown how to use the inhaler by a physician or other health care professionals.

Symptoms: High doses of tiotropium may lead to anticholinergic signs and symptoms.
No relevant adverse events, beyond dry mouth/throat and dry nasal mucosa in a dose- dependent [10-40 µg daily] incidence, were observed following 14-day dosing of up to 40 µg tiotropium inhalation solution in healthy subjects with the exception of pronounced reduction in salivary flow from day 7 onwards. No significant undesirable effects have been observed in six long term studies in COPD patients when a daily dose of 10 µg tiotropium inhalation solution was given over 4-48 weeks.
An overdose of olodaterol is likely to lead to exaggerated effects typical of beta₂-adrenergic agonists, i.e. myocardial ischemia, hypertension or hypotension, tachycardia, arrhythmias, palpitation, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, muscle spasms, nausea, fatigue, malaise, hypokalaemia, hyperglycaemia and metabolic acidosis.
Therapy: Treatment with SPIOLTO RESPIMAT should be discontinued. Supportive and symptomatic treatment is indicated. Serious cases should be hospitalized. Use of cardioselective beta-blockers may be considered, but only subject to extreme caution since the use of beta-adrenergic blocker medication may provoke bronchospasm.

SPIOLTO RESPIMAT is contraindicated in patients with hypersensitivity to tiotropium or olodaterol or to any of the excipients.
SPIOLTO RESPIMAT is also contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, e.g. ipratropium or oxitropium.

ASTHMA-RELATED DEATH: Long-acting beta₂-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large, placebo-controlled US study that compared the safety of another long-acting beta₂-adrenergic agonist (salmeterol) to placebo added to patients' usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including olodaterol, one of the active ingredients in SPIOLTO RESPIMAT.
SPIOLTO RESPIMAT is only indicated for COPD. The safety and efficacy of SPIOLTO RESPIMAT in patients with asthma have not been established. SPIOLTO RESPIMAT is not indicated for the treatment of asthma.

SPIOLTO RESPIMAT should not be used more frequently than once daily.
Asthma: SPIOLTO RESPIMAT should not be used in asthma. The efficacy and safety of SPIOLTO RESPIMAT in asthma have not been studied in this indication.
The long-term efficacy and safety of olodaterol in the treatment of asthma have not been studied. LABAs may increase the risk of asthma-related hospitalisations and death. Data from a large placebo-controlled study that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABAs, including olodaterol, one of the active ingredients in SPIOLTO RESPIMAT.
Acute bronchospasm: SPIOLTO RESPIMAT is not indicated for the treatment of acute episodes of bronchospasm, i.e. as rescue therapy.
Deterioration of disease and acute episodes: SPIOLTO RESPIMAT should not be initiated in patients with acutely deteriorating COPD. In this case, the patient's COPD management plan should direct the patient to seek medical advice immediately, and a re-evaluation of the patient and the COPD treatment regimen should be undertaken. Increasing the daily dosage of SPIOLTO RESPIMAT beyond the recommended dose is not appropriate.
Hypersensitivity: As with all medications, immediate hypersensitivity reactions may occur after administration of SPIOLTO RESPIMAT.
Paradoxical bronchospasm: As with other inhaled medicines SPIOLTO RESPIMAT may result in paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs SPIOLTO RESPIMAT should be discontinued immediately and alternative therapy substituted.
Narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction: Consistent with the anticholinergic activity of tiotropium, SPIOLTO RESPIMAT should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction. In a meta-analysis of placebo-controlled trials, tiotropium was associated with a non-significant increase in the risk of urinary retention, and a significant increase in the risk of micturition difficulties.
Patients with renal impairment: Because tiotropium is a predominantly renally excreted drug, SPIOLTO RESPIMAT use should be monitored closely in patients with moderate to severe renal impairment (creatinine clearance of <50 ml/min) (see Dosage & Administration).
Eye symptoms: Patients must be instructed in the correct administration of SPIOLTO RESPIMAT. Care must be taken not to allow the solution or mist to enter into the eyes. Eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop specialist advice should be sought immediately.
Miotic eye drops are not considered to be effective treatment.
Systemic effects: SPIOLTO RESPIMAT contains a long acting beta₂-adrenergic agonist. Long acting beta₂-adrenergic agonists should be administered with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, hypertrophic obstructive cardiomyopathy and hypertension; in patients with convulsive disorders or thyrotoxicosis, in patients with known or suspected prolongation of the QT interval; and in patients who are unusually responsive to sympathomimetic amines.
Cardiovascular effects: Like other beta₂-adrenergic agonists, olodaterol may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. In case such effects occur, treatment may need to be discontinued. In addition, beta-adrenergic agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave and ST segment depression, although the clinical significance of these observations is unknown.
Patients with a history of myocardial infarction during the previous year, unstable or life-threatening cardiac arrhythmia, hospitalised for heart failure during the previous year or with a diagnosis of paroxysmal tachycardia (>100 beats per minute) were excluded from the clinical trials. Therefore the experience in these patient groups is limited. SPIOLTO RESPIMAT should be used with caution in these patient groups.
Hypokalaemia: Beta₂-adrenergic agonists may produce significant hypokalaemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment (see Interactions), which may increase the susceptibility to cardiac arrhythmias.
Hyperglycaemia: Inhalation of high doses of beta₂-adrenergic agonists may produce increases in plasma glucose.
Others: SPIOLTO RESPIMAT should not be used in conjunction with any other medication containing LABAs or LAMAs (see Interactions). Patients who have been taking inhaled, short acting beta₂-adrenergic agonists on a regular basis (e.g. four times a day) should be instructed to use them only for symptomatic relief of acute respiratory symptoms.
Benzalkonium chloride: This medicine contains 0.0011 mg benzalkonium chloride in each actuation.
Benzalkonium chloride may cause wheezing and breathing difficulties (bronchospasm), especially if the patient has asthma. Patients with asthma are at an increased risk for these adverse events.
Driving and Using Machines: No studies on the effects on the ability to drive and use machines have been performed.
However, patients should be advised that dizziness and blurred vision have been reported with the use of SPIOLTO RESPIMAT. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience such symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.

Pregnancy: Tiotropium: There is a 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 Pharmacology: Toxicology under Actions).
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 Pharmacology: Toxicology under Actions).
The inhibitory effect of beta-adrenergic agonists, like olodaterol a component of SPIOLTO RESPIMAT on uterine contraction should be taken into account.
As a precautionary measure, it is preferable to avoid the use of SPIOLTO RESPIMAT during pregnancy.
Lactation: Clinical data from nursing women exposed to tiotropium and/or olodaterol are not available.
In preclinical studies for both tiotropium and olodaterol the substances and/or its metabolites have been detected in the milk of lactating rats, but it is not known whether tiotropium and/or olodaterol pass into human breast milk.
A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with SPIOLTO RESPIMAT should be made taking into account the benefit of breast-feeding to the child and the benefit of SPIOLTO RESPIMAT therapy to the woman.
Fertility: Clinical data on fertility are not available for tiotropium and olodaterol or the combination of both components. Preclinical studies performed with the individual components tiotropium and olodaterol showed no indication of any adverse effect on fertility (see Pharmacology: Toxicology under Actions).

The safety of SPIOLTO RESPIMAT has been evaluated in active-controlled, parallel-group and cross-over clinical trials in overall 7,151 patients with COPD. A total of 1,988 patients with COPD received the target dose of 5 microgram tiotropium and 5 microgram olodaterol.
Side effects of SPIOLTO RESPIMAT were primarily identified from data obtained in 2 active controlled, parallel-group, long-term treatment (52 weeks) clinical trials in COPD patients.
In the pooled analysis of these long-term clinical trials the overall incidence of adverse events in patients treated with SPIOLTO RESPIMAT was comparable to patients treated with the mono components tiotropium at a dose of 5 microgram or olodaterol at a dose of 5 microgram (74%, 73.3% and 76.6%, respectively). All undesirable effects previously reported with one of the individual components are considered undesirable effects with SPIOLTO RESPIMAT and are included in the adverse reactions listed as follows.
Table 10 shows all adverse events that occurred with an incidence of >2% with SPIOLTO RESPIMAT treatment group and a higher incidence rate than the active comparator groups listed. The rates are derived from all reported adverse events of that type, regardless if considered drug-related or not by the clinical investigator. (See Table 10).


Click on icon to see table/diagram/image


Adverse reactions reported in all clinical trials with SPIOLTO RESPIMAT with a frequency of less than 2% are shown as follows according to system organ class. These also include all adverse reactions previously reported with one of the individual components.
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000).
Infections and infestations: Rare: nasopharyngitis.
Metabolism and nutrition disorders: Not known: dehydration.
Nervous system disorders: Uncommon: dizziness, insomnia.
Eye disorders: Rare: vision blurred.
Not known: glaucoma, intraocular pressure increased.
Cardiac disorders: Uncommon: atrial fibrillation, palpitations, tachycardia.
Rare: supraventricular tachycardia.
Vascular disorders: Uncommon: hypertension.
Respiratory, thoracic and mediastinal disorders: Uncommon: cough.
Rare: epistaxis, pharyngitis, dysphonia, laryngitis.
Not known: bronchospasm, sinusitis.
Gastrointestinal disorders: Common: dry mouth.
Uncommon: constipation.
Rare: oropharyngeal candidiasis, gingivitis.
Not known: dysphagia, gastro-oesophageal reflux disease, glossitis, stomatitis, intestinal obstruction incl. ileus paralytic.
Skin and subcutaneous disorders: Rare: pruritus, angioneurotic oedema, urticaria, hypersensitivity (including immediate reactions).
Not known: rash, skin infection and skin ulcer, dry skin.
Musculoskeletal and connective tissue disorders: Rare: back pain¹, arthralgia.
Not known: joint swelling.
Renal and urinary disorders: Rare: urinary retention (usually in men with predisposing factors), dysuria.
Not known: urinary tract infection.
¹ Undesirable effects reported with SPIOLTO RESPIMAT, but not with the individual components.
Many of the listed adverse effects can be assigned to either the anticholinergic properties of tiotropium or to the β-adrenergic properties of olodaterol, the components of SPIOLTO RESPIMAT.
In addition the occurrence of other undesirable effects related to the beta-adrenergic agonist class, which are not listed previously, should be taken into consideration, such as arrhythmia, myocardial ischaemia, angina pectoris, hypotension, tremor, headache, nervousness, nausea, muscle spasms, fatigue, malaise, hypokalaemia, hyperglycaemia, and metabolic acidosis.

Tiotropium: Although no formal drug interaction studies have been performed, tiotropium bromide has been used concomitantly with other drugs commonly used in the treatment of COPD, methylxanthines, oral and inhaled steroids, without clinical evidence of drug interactions.
The chronic co-administration of tiotropium bromide with other anticholinergic drugs has not been studied. Therefore, the chronic co-administration of other anticholinergic drugs with SPIOLTO RESPIMAT is not recommended.
Olodaterol: In vitro studies indicated pharmacokinetic drug interactions involving CYP450 enzymes are not expected. Inhibitors of P-glycoprotein, OAT1, OAT3 or OCT1 may alter the systemic exposure to or disposition of olodaterol. Olodaterol was not an inhibitor of these transporters at clinically-relevant concentrations.
Adrenergic agents: Concomitant administration of other adrenergic agents may potentiate the undesirable effects of SPIOLTO RESPIMAT.
Xanthine Derivatives, Steroids or Diuretics: Concomitant treatment with xanthine derivatives, steroids, or non-potassium sparing diuretics may potentiate any hypokalemic effect of adrenergic agonists (see Precautions).
Beta-blockers: Beta-adrenergic blockers may weaken or antagonize the effect of olodaterol. Cardioselective beta-blockers could be considered, although they should be administered with caution.
MAO Inhibitors, Tricyclic Antidepressants, QTc prolonging drugs: Monoamine oxidase inhibitors, or tricyclic antidepressants or other drugs known to prolong the QTc interval may potentiate the action of SPIOLTO RESPIMAT on the cardiovascular system.
Pharmacokinetic Drug Drug interactions: In a drug interaction study with olodaterol using the strong dual CYP and P-gp inhibitor ketoconazole a 1.7-fold increase of systemic exposure was observed (see Pharmacology: Pharmacokinetics under Actions). No safety concerns were identified in clinical studies of up to one year with olodaterol at doses up to twice the recommended therapeutic dose. No dose adjustment of SPIOLTO RESPIMAT is necessary.

Instructions for Use: The patient will need to use this inhaler only ONCE A DAY. The patient should take TWO PUFFS each use.
If SPIOLTO RESPIMAT has not been used for more than 7 days release one puff towards the ground.
If SPIOLTO RESPIMAT has not been used for more than 21 days repeat steps 4 to 6 under 'Prepare for first use' until a cloud is visible. Then repeat steps 4 to 6 three more times.
How to care for the SPIOLTO RESPIMAT: Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or tissue only, at least once a week.
Any minor discoloration in the mouthpiece does not affect the SPIOLTO RESPIMAT inhaler performance.
When to get a new SPIOLTO RESPIMAT: The SPIOLTO RESPIMAT inhaler contains 60 puffs (30 doses) if used as indicated (two puffs/Once daily).
The dose indicator shows approximately how much medication is left.
When the dose indicator enters the red area of the scale the patient needs to get a new prescription; there is approximately medication for 7 days left (14 puffs).
Once the dose indicator reaches the end of the red scale, the SPIOLTO RESPIMAT locks automatically - no more doses can be released. At this point, the clear base cannot be turned any further.
Three months after first use, the SPIOLTO RESPIMAT should be discarded even if it has not been used.
Prepare for first use: 1. Remove clear base: Keep the cap closed.
Press the safety catch while firmly pulling off the clear base with the other hand.
2. Insert cartridge: Insert the narrow end of the cartridge into the inhaler.
Place the inhaler on a firm surface and push down firmly until it snaps into place.
3. Replace clear base: Put the clear base back into place until it clicks.
4. Turn: Keep the cap closed.
Turn the clear base in the direction of the arrows on the label until it clicks (half a turn).
5. Open: Open the cap until it snaps fully open.
6. Press: Point the inhaler toward the ground.
Press the dose-release button.
Close the cap.
Repeat steps 4-6 until a cloud is visible.
After a cloud is visible, repeat steps 4-6 three more times.
Daily use: TURN: Keep the cap closed.
TURN the clear base in the direction of the arrows on the label until it clicks (half a turn).
OPEN: OPEN the cap until it snaps fully open.
PRESS: Breathe out slowly and fully. Close the lips around the mouthpiece without covering the air vents.
While taking a slow, deep breath through the mouth, PRESS the dose-release button and continue to breathe in.
Hold breath for 10 seconds or for as long as comfortable. Repeat Turn, Open, Press for a total of 2 puffs.

Store below 30°C. Do not freeze.
Store in a safe place, out of the reach of children.
In-use shelf-life: 3 months after the cartridge is inserted into the RESPIMAT inhaler.

Antiasthmatic & COPD Preparations

R03AL06 - olodaterol and tiotropium bromide ; Belongs to the class of combination of adrenergics with anticholinergics, that may also include a corticosteroid. Used in the treatment of obstructive airway diseases.

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