SPIOLTO RESPIMAT Tiotropium Bromide / Olodaterol Hydrochloride 2.5mcg / 2.5mcg per puff Solution for Oral Inhalation 30doses

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 Tiotropium bromide + Olodaterol HCl (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.

 

Pregnancy: There is a limited amount of data from the use of tiotropium in pregnant women. For olodaterol, no clinical data on exposed pregnancies are available.
Preclinical studies with tiotropium do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses (please refer to Pharmacology: Toxicology under Actions).
Preclinical data for olodaterol revealed effects typical for beta-adrenergic agonists at high multiples of the therapeutic doses (please refer to Pharmacology: Toxicology under Actions).
As a precautionary measure, it is preferable to avoid the use of Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) during pregnancy.
The inhibitory effect of beta-adrenergic agonists, like olodaterol, a component of Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) on uterine contraction should be taken into account.
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.
Therefore, Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) should not be used in nursing women unless the expected benefit outweighs any possible risk to the infant.
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 (please refer to Pharmacology: Toxicology under Actions).

 

Store at temperatures not exceeding 30°C.
Do not freeze.
Recommended use: 6 cartridges per inhaler.
Use within three months after the cartridge is inserted into the inhaler.

 

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with anticholinergics. ATC code: RO3ALxx.
Pharmacology: Pharmacodynamics: Mode of action: Tiotropium, a long-acting muscarinic antagonist and olodaterol a long acting beta₂-adrenergic are administered together in the Tiotropium bromide + Olodaterol HCl (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 lungs.
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: The effect of tiotropium (inhalation powder 18 and 54 microgram once daily) on the QT/QTc interval of the ECG was investigated in 56 healthy male and female volunteers in a double-blind, randomised, placebo- and active (moxifloxacin) controlled study. The mean changes from baseline in QT interval over 5 minutes to 2 hours after dosing on day 12 was -1.4 ms for placebo, +0.6 ms for 18 microgram tiotropium and -2.1 ms for 54 microgram tiotropium; the upper limit of the one-sided 95% confidence intervals of the placebo-adjusted difference from baseline was less than 10 ms for both tiotropium doses (+4.9 ms for 18 microgram tiotropium, +2.2 ms for 54 microgram tiotropium).
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.
Tiotropium + Olodaterol (Spiolto Respimat): In two 52-week randomized, double-blind trials using Tiotropium bromide + Olodaterol HCl (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 Tiotropium bromide + Olodaterol HCl (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 Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) included three randomised, double-blind trials: (i) two replicate, 52 week parallel group trials comparing Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) with tiotropium 5 microgram and olodaterol 5 microgram (1029 received Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) [Trials 1 and 2]; (ii) one 6 week cross-over trial comparing Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) with tiotropium 5 microgram and olodaterol 5 microgram and placebo (139 received Tiotropium bromide + Olodaterol HCl (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 postdose in a sub-set of patients) and at 23-24 hrs post-dose; the primary lung function efficacy endpoints were change from pretreatment 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 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 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, Tiotropium bromide + Olodaterol HCl (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 Tiotropium bromide + Olodaterol HCl (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 Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) compared to tiotropium 5 microgram and olodaterol 5 microgram (Table 1). (See Table 1.)

The increased bronchodilator effects of Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) compared to tiotropium 5 microgram and olodaterol 5 microgram were maintained throughout the 52 week treatment period. Tiotropium bromide + Olodaterol HCl (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, Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) showed a significantly greater FEV₁ response compared to tiotropium 5 microgram and olodaterol 5 microgram over the full 24 hour dosing interval (Figure 1, Table 2). (See Figure 1 and Table 2.)

In the 6 week trial, Tiotropium bromide + Olodaterol HCl (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 (Figure 2, Table 3). (See Figure 2 and Table 3.)

Dyspnoea: After 24 weeks (Trials 1 and 2), Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) significantly improved mean TDI focal score compared to tiotropium 5 microgram and olodaterol 5 microgram (Table 5). More patients treated with Tiotropium bromide + Olodaterol HCl (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 4.)

Rescue Medication Use: Patients treated with Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) used less daytime and night-time rescue salbutamol compared to patients treated with tiotropium 5 microgram and olodaterol 5 microgram (Trials 1 and 2).
Patient Global Rating: Patients treated with Tiotropium bromide + Olodaterol HCl (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 data set, the proportion of patients experiencing a moderate/severe COPD exacerbation was 27.7% for Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) and 28.8% for tiotropium 5 microgram.
In a one-year, randomised, double-blind, active-controlled parallel group clinical trial (Trial 9) Tiotropium bromide + Olodaterol HCl (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 Tiotropium bromide + Olodaterol HCl (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.
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".
Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) treatment resulted in an additional 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 was designed to reach a significance level of 1%.
Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) treatment resulted reduction in an 11% lower annualised rate of hospitalisations due to a COPD exacerbation (RR 0.89, 95% CI 0.76- 1.03, p=0.1265). Beyond this Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) treatment resulted in a 20% lower annualised rate of moderate to severe exacerbation that required treatment with systemic corticosteroids (RR 0.80, 95% CI 0.68-0.94, p=0.0068) and in a 9% lower annualised rate of moderate to severe exacerbation that required treatment with systemic corticosteroids and antibiotics (RR 0.91, 95% Cl 0.83-1.00, p=0.0447). Treatment with Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) did not result in a reduction in the rate of moderate to severe exacerbations treated with antibiotics only (RR 1.07, 95% CI 0.96-1.20, p=0.2062).
Time to all-cause mortality was included as a secondary endpoint in this trial. There was no significant difference in the risk of all-cause mortality between Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) and tiotropium 5 microgram. During the actual treatment period (i.e. on-treatment plus one day) 36 versus 32 deaths were observed (Hazard Ratio (HR) 1.09, 95% CI, 0.67, 1.75, p=0.7357) while during the planned study period (381 days) 107 versus 121 deaths were observed (HR 0.88, 95% CI, 0.68, 1.15, p=0.3485) for Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) and tiotropium 5 microgram, respectively.
The analysis of the additional exacerbation trial (Trial 9) is displayed in Table 5. (See Table 5.)

Health-related Quality of Life: After 24 weeks (Trials 1 and 2), Tiotropium bromide + Olodaterol HCl (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 Tiotropium bromide + Olodaterol HCl (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 6.)

In two additional 12-week (Trials 7 and 8), placebo-controlled clinical trials, 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, Tiotropium bromide + Olodaterol HCl (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 Tiotropium bromide + Olodaterol HCl (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).
In Trial 9, treatment with Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) provided improvements in the COPD Assessment Test score (CAT, a measure of health-related quality of life) versus tiotropium 5 microgram at all study visits (adjusted mean difference versus tiotropium from -0.7 (95% CI (-1.0, -0.5)) at day 90 to -0.4 (95% CI (-0.7,-0.1)) at day 360, all p<0.01). In a responder analysis the proportion of patients experiencing a clinically meaningful improvement in CAT (defined as a reduction of 2 points or more) was larger with Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) versus tiotropium 5 microgram (44.51% vs 40.77% respectively, odds ratio 1.17, 95% CI 1.06-1.28 p<0.001).
Inspiratory capacity, breathing discomfort and exercise endurance: The effect of Tiotropium bromide + Olodaterol HCl (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 Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) with tiotropium 5 microgram, olodaterol 5 microgram and placebo during constant work rate cycling (450 received Tiotropium bromide + Olodaterol HCl (Spiolto Respimat)) [Trials 4 and 5]; (ii) one 12 week parallel group trial comparing Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) with placebo during constant work rate cycling (139 received Tiotropium bromide + Olodaterol HCl (Spiolto Respimat)) and constant speed walking (sub-set of patients) [Trial 6].
Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) significantly improved inspiratory capacity compared to tiotropium 5 microgram, olodaterol 5 microgram and placebo after 6 weeks (Trials 4 and 5; Table 7) and compared to placebo after 12 weeks (0.234 L, p<0.0001; Trial 6). (See Table 7.)

In Trials 4 and 5, Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) improved endurance time during constant work rate cycling by 20.9% and 13.4% compared to placebo (Table 8). In Trial 6, Tiotropium bromide + Olodaterol HCl (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 and increased endurance time during constant speed walking (in a sub-set of patients) by 20.6% after 6 weeks and by 20.9% after 12 weeks compared to placebo (Table 9). (See Tables 8 and 9.)

In Trials 4 and 5, Tiotropium bromide + Olodaterol HCl (Spiolto Respimat) decreased the slope of breathing discomfort during constant work rate cycling compared to placebo (p<0.0005; Table 10). (See Table 10.)

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 (CL_cr >80 mL/min). In subjects with moderate to severe renal impairment (CL_CR <50 mL/min), intravenous administration of tiotropium resulted in two-fold 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: 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%.
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 ß-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 AU_C(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.
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.
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.