Spiriva Handihaler/Spiriva Respimat

Spiriva Handihaler: 1 capsule for inhalation contains tiotropium bromide 18 mcg equivalent to 22.5 mcg tiotropium bromide monohydrate.
Spiriva Respimat: The delivered dose is 2.5 μg tiotropium per puff (2 puffs per dose).
2.5 μg tiotropium is equivalent to 3.124 μg tiotropium bromide monohydrate.
(INN = tiotropium bromide).
Excipients/Inactive Ingredients: Spiriva Handihaler: lactose monohydrate (which contains milk protein).
Spiriva Respimat: benzalkonium chloride, disodium edetate, water, purified, hydrochloric acid for pH adjustment.

Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, anticholinergics. ATC Code: R03BB04.
Mode of Action: Tiotropium bromide is a long-acting, specific antimuscarinic agent, 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 non-clinical in vitro as well as in vivo studies bronchoprotective effects were dose-dependent and lasted longer than 24 hours. The long duration of 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 and asthma. The bronchodilation following inhalation of tiotropium is primarily a local effect (on the airways) not a systemic one.
Spiriva Handihaler: Cardiac electrophysiology: In a dedicated QT study involving 53 healthy volunteers, SPIRIVA 18 mcg and 54 mcg (i.e. three times the therapeutic dose) over 12 days did not prolong QT intervals of the ECG.
Spiriva Respimat: Clinical Trials: COPD: The clinical Phase III programme for COPD included two 1-year, two 12-weeks and two 4-weeks randomised, double-blind studies in 2901 COPD patients (1038 receiving the 5 μg tiotropium dose). The 1-year programme consisted of two placebo-controlled trials. The two 12-week trials were both active (ipratropium) - and placebo-controlled. All six studies included lung function measurements. In addition, the two 1-year studies included health outcome measures of dyspnoea, health-related quality of life and effect on exacerbations.
Pharmacodynamics: N/A.
Clinical Trials: Spiriva Handihaler: Clinical efficacy: The clinical development program included four one-year and two six-month randomised, double-blind studies in 2663 patients with COPD (1308 receiving SPIRIVA). The one-year program consisted of two placebo-controlled and two ipratropium-controlled trials. The six-month trials were both salmeterol- and placebo-controlled. These studies included evaluation of lung function, dyspnoea, exacerbations of COPD and patients assessments of their health-related quality of life.
Lung function: SPIRIVA administered once daily, provided significant improvement in lung function (forced expiratory volume in one second, FEV₁ and forced vital capacity, FVC) within 30 minutes following the first dose and was maintained for 24 hours. Pharmacodynamic steady state was reached within one week with the majority of bronchodilation observed by the third day. SPIRIVA significantly improved morning and evening peak expiratory flow rate (PEFR) as measured by patient's daily recordings.
The improvement in lung function with SPIRIVA was demonstrated throughout the period of administration in the six long-term trials (Figures 1-3). These improvements were maintained with no evidence of tolerance. (See Figures 1, 2 and 3.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

A randomised, placebo-controlled clinical study in 105 patients with COPD demonstrated that bronchodilation was maintained throughout the 24 hour dosing interval in comparison to placebo regardless of whether SPIRIVA was administered in the morning or in the evening.
Long-term clinical trials (6 months and 1 year): Dyspnoea, Exercise tolerance: SPIRIVA significantly improved dyspnoea (as evaluated using the Transition Dyspnoea Index). This improvement was maintained throughout the treatment period.
The impact of improvement in dyspnoea on functional activities was investigated in two randomised double blind placebo controlled trials in COPD patients. In these trials SPIRIVA significantly improved symptom limited exercise tolerance by 19.7% and 28.3% compared with placebo.
Health-related Quality of Life: SPIRIVA significantly improved health-related quality of life as demonstrated by the disease-specific St. George's Respiratory Questionnaire. This improvement was maintained throughout the treatment period.
COPD Exacerbations: SPIRIVA significantly reduced the number of COPD exacerbations and delayed the time to first exacerbation in comparison to placebo.
Additionally, in the one-year placebo controlled trials SPIRIVA significantly reduced the number of hospitalisations associated with COPD exacerbations and delayed the time to first hospitalisation.
A one-year randomised, double-blind, double-dummy, parallel-group trial compared the effect of treatment with 18 mcg of SPIRIVA once daily with that of 50 mcg of salmeterol HFA pMDI twice daily on the incidence of moderate and severe exacerbations in 7,376 patients with COPD and a history of exacerbations in the preceding year. (See Figures 4-5 and Table 1.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Compared with salmeterol, SPIRIVA increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). SPIRIVA also increased the time to the first severe (hospitalised) exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe (hospitalised) exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002), and reduced the annual number of severe (hospitalised) exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001).
Long term clinical trials (>1 up to 4 years): In a 4-year trial of 5,993 patients SPIRIVA maintained improvements in FEV₁ throughout 4 years but did not alter the annualized rate of decline of FEV₁. (See Figure 6.)

Click on icon to see table/diagram/image

During treatment, there was a 16% reduction in the risk of death. The incidence rate of death was 4.79 per 100 patient years in the placebo group vs. 4.10 per 100 patient years in the tiotropium group (hazard ratio (tiotropium/placebo) = 0.84, 95% CI = 0.73, 0.97). Treatment with tiotropium reduced the risk of respiratory failure by 19% (2.09 vs. 1.68 cases per 100 patient years, relative risk (tiotropium/placebo) = 0.81, 95% CI = 0.65, 1.00).
Long-term tiotropium active-controlled study: A long term, large scale, randomised, double-blind, active-controlled study with a treatment period up to 3 years has been performed to compare the efficacy and safety of SPIRIVA RESPIMAT and SPIRIVA HandiHaler (5,711 patients receiving SPIRIVA RESPIMAT 2.5 microgram (5 microgram medicinal dose); 5,694 patients receiving SPIRIVA HandiHaler). The primary endpoints were time to first COPD exacerbation, time to all-cause mortality and in a sub-study (906 patients) trough FEV₁ (pre-dose).
The time to first COPD exacerbation was similar during the study with SPIRIVA RESPIMAT and SPIRIVA HandiHaler (hazard ratio (SPIRIVA RESPIMAT / SPIRIVA HandiHaler) 0.98 with a 95% CI of 0.93 to 1.03). The median number of days to the first COPD exacerbation was 756 days for SPIRIVA RESPIMAT and 719 days for SPIRIVA HandiHaler.
The bronchodilator effect of SPIRIVA RESPIMAT was sustained over 120 weeks, and was similar to SPIRIVA HandiHaler. The mean difference in trough FEV₁ for SPIRIVA RESPIMAT versus SPIRIVA HandiHaler was -0.010 L (95% CI -0.038 to 0.018 mL).
All-cause mortality was similar during the study with SPIRIVA RESPIMAT and SPIRIVA HandiHaler (hazard ratio (SPIRIVA RESPIMAT / SPIRIVA HandiHaler) 0.96 with a 95% CI of 0.84 to 1.09).
Spiriva Respimat: COPD: The clinical Phase III programme for COPD included two 1-year, two 12-weeks and two 4-weeks randomised, double-blind studies in 2901 COPD patients (1038 receiving the 5 μg tiotropium dose). The 1-year programme consisted of two placebo-controlled trials. The two 12-week trials were both active (ipratropium) - and placebo-controlled. All six studies included lung function measurements. In addition, the two 1-year studies included health outcome measures of dyspnoea, health-related quality of life and effect on exacerbations.
Placebo-controlled studies: Lung function: SPIRIVA RESPIMAT, administered once daily, provided significant improvement in lung function (forced expiratory volume in one second and forced vital capacity) within 30 minutes following the first dose, compared to placebo. Improvement of lung function was maintained for 24 hours at steady state.
Pharmacodynamic steady state was reached within one week. SPIRIVA RESPIMAT significantly improved morning and evening PEFR (peak expiratory flow rate) as measured by patient's daily recordings. The use of SPIRIVA RESPIMAT resulted in a reduction of rescue bronchodilator use compared to placebo.
The bronchodilator effects of SPIRIVA RESPIMAT were maintained throughout the 48-week period of administration with no evidence of tolerance. (See Figures 7, 8 and 9.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

A combined analysis of two randomised, placebo-controlled, crossover, clinical studies demonstrated that the bronchodilator response for SPIRIVA RESPIMAT (5 μg) was numerically higher compared to SPIRIVA HandiHaler (18 μg) inhalation powder after a 4-week treatment period.
Dyspnoea, Health-related Quality of Life, COPD Exacerbations in long-term 1 year studies: (a) SPIRIVA RESPIMAT significantly improved dyspnoea (as evaluated using the Transition Dyspnoea Index). An improvement was maintained throughout the treatment period.
(b) Patients' evaluation of their Quality of Life (as measured using the St. George's Respiratory Questionnaire) showed that SPIRIVA RESPIMAT had positive effects on the psychosocial impacts of COPD, activities affected by COPD and distress due to COPD symptoms.
The improvement in mean total score between SPIRIVA RESPIMAT versus placebo at the end of the two 1-year studies was statistically significant and maintained throughout the treatment period.
(c) COPD Exacerbations: In three one-year, randomised, double-blind, placebo-controlled clinical trials SPIRIVA RESPIMAT treatment resulted in a significantly reduced risk of a COPD exacerbation in comparison to placebo. Exacerbations of COPD were defined as "a complex of at least two respiratory events/symptoms with a duration of three days or more requiring a change in treatment (prescription of antibiotics and/or systemic corticosteroids and/or a significant change of the prescribed respiratory medication)". SPIRIVA RESPIMAT treatment resulted in a reduced risk of a hospitalisation due to a COPD exacerbation (significant in the appropriately powered large exacerbation trial).
The pooled analysis of two Phase III trials and separate analysis of an additional exacerbation trial is displayed in Table 2. All respiratory medications except anticholinergics and long-acting beta-agonists were allowed as concomitant treatment, i.e. rapidly acting beta-agonists, inhaled corticosteroids and xanthines. Long-acting beta-agonists were allowed in addition in the exacerbation trial. (See Table 2.)

Click on icon to see table/diagram/image

Long-term tiotropium active-controlled study: A long term, large scale, randomised, double-blind, active-controlled study with a treatment period up to 3 years has been performed to compare the efficacy and safety of SPIRIVA RESPIMAT and SPIRIVA HANDIHALER (5,711 patients receiving SPIRIVA RESPIMAT 2.5 microgram (5 microgram medicinal dose); 5,694 patients receiving SPIRIVA HANDIHALER). The primary endpoints were time to first COPD exacerbation, time to all-cause mortality and in a sub-study (906 patients) trough FEV₁ (pre-dose).
The time to first COPD exacerbation was similar during the study with SPIRIVA RESPIMAT and SPIRIVA HANDIHALER (hazard ratio (SPIRIVA RESPIMAT / SPIRIVA HANDIHALER) 0.98 with a 95% CI of 0.93 to 1.03). The median number of days to the first COPD exacerbation was 756 days for SPIRIVA RESPIMAT and 719 days for SPIRIVA HANDIHALER.
The bronchodilator effect of SPIRIVA RESPIMAT was sustained over 120 weeks, and was similar to SPIRIVA HANDIHALER. The mean difference in trough FEV₁ for SPIRIVA RESPIMAT versus SPIRIVA HANDIHALER was -0.010 L (95% CI -0.038 to 0.018 mL).
All-cause mortality was similar during the study with SPIRIVA RESPIMAT and SPIRIVA HANDIHALER (hazard ratio (SPIRIVA RESPIMAT / SPIRIVA HANDIHALER) 0.96 with a 95% CI of 0.84 to 1.09).
Asthma: Adult patients: The clinical Phase III programme for persistent asthma included two 1-year, two 6-month and one 12-week, randomised, double-blind, placebo-controlled studies in a total of 3,476 asthma patients (1,128 receiving SPIRIVA RESPIMAT) on background treatment of at least ICS or ICS/LABA. The two 6-month studies were also active-controlled (salmeterol). All 5 studies included lung function measurements, assessments of symptoms including exacerbations, and health-related quality of life.
In the two 1-year PrimoTinA-asthma studies in patients who were symptomatic on maintenance treatment of at least high-dose ICS plus LABA, SPIRIVA RESPIMAT showed significant improvements in lung function over placebo when used as add-on to background treatment.
At week 24, mean improvements in peak and trough FEV₁ were 0.110 litres (95% CI: 0.063 to 0.158 litres, p<0.0001) and 0.093 litres (95% CI: 0.050 to 0.137 litres, p<0.0001), respectively.
The improvement of lung function compared to placebo was maintained for 24 hours (see Figure 10).

Click on icon to see table/diagram/image

At week 24, SPIRIVA RESPIMAT significantly improved morning and evening peak expiratory flow (PEF; mean improvement in the morning 23 L/min; 95% CI: 16 to 29 L/min, p<0.0001; evening 26 L/min; 95% CI: 20 to 33 L/min, p<0.0001).
The bronchodilator effects of SPIRIVA RESPIMAT were maintained throughout the 1 year period of administration with no evidence of tachyphylaxis or tolerance (see Figure 11).

Click on icon to see table/diagram/image

SPIRIVA RESPIMAT significantly reduced the risk of severe asthma exacerbations (see Table 3 and Figure 12).

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

The Asthma Control Questionnaire (ACQ) responder rates defined as percentage of patients improving by at least 0.5 points, were significantly higher with SPIRIVA RESPIMAT (53.9% versus 46.9%; p=0.0427).
The Asthma Quality of Life Questionnaire (AQLQ(S)) mean scores for SPIRIVA RESPIMAT improved significantly over placebo at week 24.
In the two 6-month MezzoTinA-asthma studies in patients who were symptomatic on maintenance treatment of medium-dose ICS, SPIRIVA RESPIMAT showed significant improvements in lung function over placebo when used as add-on to background treatment.
At week 24, mean improvements in peak and trough FEV₁ were 0.185 litres (95% CI: 0.146 to 0.223 litres, p<0.0001) and 0.146 litres (0.105 to 0.188 litres, p<0.0001), respectively. The peak and trough FEV₁ values for salmeterol were 0.196 litres (95% CI: 0.158 to 0.234 litres) and 0.114 litres (95% CI: 0.073 to 0.155 litres), respectively.
SPIRIVA RESPIMAT significantly improved morning and evening PEF (morning 24 L/min; 95% CI: 18 to 31 L/min, p<0.0001; evening 23 L/min; 95% CI: 17 to 30 L/min, p<0.0001). The morning and evening PEF for salmeterol compared to placebo were 25 L/min (95% CI: 19 to 31 L/min) and 21 L/min (95% CI: 15 to 27 L/min), respectively.
Patients who took SPIRIVA RESPIMAT had a significantly higher ACQ responder rate at week 24 compared to patients taking placebo (see Table 4).

Click on icon to see table/diagram/image

In the 12 week GraziaTinA-asthma study in patients who were symptomatic on maintenance treatment with low dose ICS, SPIRIVA RESPIMAT showed significant improvements in lung function over placebo when used as add-on to background treatment. At 12 weeks, the mean improvements in peak and trough FEV₁ were 0.128 litres (95% CI: 0.057 to 0.199 litres, p<0.0005) and 0.122 litres (95% CI: 0.049 to 0.194 litres, p<0.0010), respectively.
Paediatric Patients: The clinical Phase III program for persistent asthma in paediatric patients (1-17 years) included: Adolescents (12-17 years): one 1-year and one 12-week randomised, double-blind, placebo-controlled studies in a total of 789 asthma patients (264 receiving SPIRIVA RESPIMAT).
Children (6-11 years): one 1-year and one 12-week randomised, double-blind, placebo-controlled studies in a total of 801 asthma patients (265 receiving SPIRIVA RESPIMAT).
Children (1-5 years): one 12-week randomised, double-blind placebo-controlled study in a total of 101 asthma patients (31 receiving SPIRIVA RESPIMAT).
In all these studies, patients were on background treatment of at least ICS.
Adolescents (12-17 years): In the 1-year RubaTinA-asthma study in patients who were symptomatic on maintenance treatment of at least medium-dose ICS, SPIRIVA RESPIMAT showed significant improvements in lung function over placebo when used as add-on to background treatment.
At week 24, mean improvements in peak and trough FEV1 were 0.174 litres (95% CI: 0.076 to 0.272 litres, p=0.0005) and 0.117 litres (95% CI: 0.010 to 0.223 litres, p=0.0320), respectively.
At week 24, SPIRIVA RESPIMAT significantly improved morning and evening PEF (morning 15.8 L/min; 95% CI: 2.3, 29.3 L/min, p=0.0214; evening 16.7 L/min; 95% CI: 3.4, 30.0 L/min, p=0.0137).
The bronchodilator effects of SPIRIVA RESPIMAT were maintained throughout the 1 year period of administration with no evidence of tachyphylaxis (see Figure 13).

Click on icon to see table/diagram/image

In the 12-week PensieTinA-asthma study in patients who were symptomatic on maintenance treatment of at least medium dose ICS in combination with 1 or more controller medication, SPIRIVA RESPIMAT showed improvements in lung function over placebo when used as add-on to background treatment, however, the differences in peak and trough FEV1 were not statistically significant.
At week 12, mean improvements in peak and trough FEV1 were 0.090 litres (95% CI: -0.019 to 0.198 litres, p=0.1039) and 0.054 litres (95% CI: -0.061 to 0.168 litres, p=0.3605), respectively.
At week 12, SPIRIVA RESPIMAT significantly improved morning and evening PEF (morning 17.4 L/min; 95% CI: 5.1 to 29.6 L/min; evening 17.6 L/min; 95% CI: 5.9 to 29.6 L/min).
Children (6-11 years): In the 1-year CanoTinA-asthma study in patients who were symptomatic on maintenance treatment of at least medium-dose ICS, SPIRIVA RESPIMAT showed significant improvements in lung function and asthma control over placebo when used as add-on to background treatment.
At week 24, mean improvements in peak and trough FEV1 were 0.164 litres (95% CI: 0.103 to 0.225 litres, p<0.0001) and 0.118 litres (95% CI: 0.048 to 0.188 litres, p=0.0010), respectively.
The bronchodilator effects of SPIRIVA RESPIMAT were maintained throughout the 1 year period of administration with no evidence of tachyphylaxis (see Figure 14).

Click on icon to see table/diagram/image

In the 12-week VivaTinA-asthma study in patients who were symptomatic on maintenance treatment of at least medium dose ICS in combination with 1 or more controller medication, SPIRIVA RESPIMAT showed significant improvements in lung function over placebo when used as add-on to background treatment.
At week 12, mean improvements in peak and trough FEV1 were 0.139 litres (95% CI: 0.075 to 0.203 litres, p<0.0001) and 0.087 litres (95% CI: 0.019 to 0.154 litres, p=0.0117), respectively.
Children (1-5 years): One 12-week randomised, double-blind, placebo-controlled, phase II/III clinical study (NinoTinA-asthma) was conducted in a total of 101 children (31 received SPIRIVA RESPIMAT) with asthma on background treatment of at least ICS.
An Aerochamber Plus Flow-Vu valved holding chamber with facemask was used to administer SPIRIVA RESPIMAT in 98 patients.
The primary objective of the study was safety; efficacy assessments were exploratory.
The number of asthma adverse events was lower for SPIRIVA RESPIMAT compared to placebo. Exploratory efficacy evaluations did not show differences for SPIRIVA RESPIMAT from placebo. Efficacy in patients 1 to 5 years of age is extrapolated from demonstrated efficacy in patients 6 years of age and older.
Pharmacokinetics: Spiriva Handihaler: Tiotropium is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium is administered by dry powder inhalation. Generally with the inhaled route of administration, the majority of the delivered dose is deposited in the gastro-intestinal tract, and to a lesser extent in the intended organ of the lung. Many of the pharmacokinetic data described below were obtained with higher doses as recommended for therapy.
Spiriva Respimat: Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium bromide is available as inhalation solution administered by the Respimat inhaler. Approximately 40% of the inhaled dose is deposited in the lungs, the target organ, the remaining amount being deposited in the gastrointestinal tract. Some of the pharmacokinetic data described below were obtained with higher doses as recommended for therapy.
Absorption: Spiriva Handihaler: Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable. Oral solutions of tiotropium have an absolute bioavailability of 2-3%. Food is not expected to influence the absorption of tiotropium for the same reason.
Maximum tiotropium plasma concentrations were observed 5 - 7 minutes after inhalation. At steady state, peak tiotropium plasma concentrations in COPD patients were 12.9 pg/mL and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 1.71 pg/mL.
Spiriva Respimat: Following inhalation by young healthy volunteers, urinary excretion data suggests that approximately 33% of the inhaled dose reaches the systemic circulation. Oral solutions of tiotropium have an absolute bioavailability of 2-3%. Food is not expected to influence the absorption of tiotropium for the same reason. Maximum tiotropium plasma concentrations were observed 5-7 minutes after inhalation. At steady state, peak tiotropium plasma concentrations of 10.5 pg/mL were achieved in COPD patients and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 1.60 pg/ml.
A steady-state tiotropium peak plasma concentration of 5.15 pg/mL was attained 5 minutes after the administration of the same dose to patients with asthma.
Distribution: Tiotropium has a plasma protein binding of 72% and shows a volume of distribution of 32 L/kg. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium does not penetrate the blood-brain barrier to any relevant extent.
Biotransformation: The extent of biotransformation is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, both not binding to muscarinic receptors.
In-vitro experiments with human liver microsomes and human hepatocytes suggest that some further drug (<20% of dose after intravenous administration) is metabolised by cytochrome P450 dependent oxidation and subsequent glutathione conjugation to a variety of Phase II-metabolites. This enzymatic pathway can be inhibited by the CYP450 2D6 (and 3A4) inhibitors, quinidine, ketoconazole and gestodene. Thus CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a smaller part of the dose. Tiotropium even in supra-therapeutic concentrations does not inhibit cytochrome P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.
Elimination: The effective half-life of tiotropium ranges between 27 to 45 h following inhalation by COPD patients. The effective half-life was 34 hours in patients with asthma. Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers. Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After dry powder inhalation to COPD patients to steady state, urinary excretion is 7% (1.3 μg) of the unchanged dose over 24 hours, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces. The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine. After chronic once daily inhalation by COPD patients, pharmacokinetic steady state was reached by day 7 with no accumulation thereafter.
Linearity/nonlinearity: Tiotropium demonstrates linear pharmacokinetics in the therapeutic range independent of the formulation.
Spiriva Respimat: After inhalation of the inhalation solution by COPD patients urinary excretion is 18.6% (0.93 μg) of the dose, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces.
In patients with asthma, 11.9% (0.595 μg) of the dose is excreted unchanged in the urine over 24 hours post dose at steady state.
Special Populations: Spiriva Handihaler: Elderly Patients: As expected for all predominantly renally excreted drugs, advancing age was associated with a decrease of tiotropium renal clearance (365 ml/min in COPD patients < 65 years to 271 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.
Renally Impaired Patients: Following once daily inhaled administrations of tiotropium to steady-state in COPD patients, with mild renal impairment (CL_CR 50-80 ml/min) resulted in slightly higher AUC0-6,ss (between 1.8 - 30% higher) and similar C_max,ss values compared to patients with normal renal function (Cl_CR > 80 mL/min).
In COPD patients with moderate to severe renal impairment (CL_CR <50 ml/min) the intravenous administration of tiotropium resulted in doubling of the plasma concentrations (82% increase in AUC_0-4h) and 52% higher C_max compared to COPD patients with normal renal function, which was confirmed by plasma concentrations after dry powder inhalation.
Hepatically Impaired Patients: 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 by simple non-enzymatic ester cleavage to products that do not bind to muscarinic receptors.
Spiriva Respimat: Elderly Patients: 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.
Exposure to tiotropium was not found to differ with age in patients with asthma.
Paediatric Patients: The peak and total exposure to tiotropium was not found to differ between paediatric patients (aged 6 to 17 years) and adults with asthma. In patients 1 to 5 years old with asthma, the total exposure as measured by urinary excretion was 52 to 60% lower than that observed in patients 6 years and older with asthma; the total exposure data when adjusted for body surface area were found to be comparable in all age groups. SPIRIVA RESPIMAT was administered with a valved holding chamber with facemask in patients 1 to 5 years of age.
Renally Impaired Patients: 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 COPD patients with moderate to severe renal impairment (CL_CR <50 mL/min) the intravenous administration of tiotropium bromide resulted in doubling of the total exposure (82% higher AUC_0-4h) and 52% higher C_max) compared to COPD patients with normal renal function, which was confirmed by plasma concentrations after dry powder inhalation.
In asthma patients with mild renal impairment (CL_CR 50-80 mL/min) inhaled tiotropium did not result in relevant increases in exposure compared to patients with normal renal function.
Hepatically Impaired Patients: 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.
Toxicology: The acute inhalation and oral toxicity in mice, rats, and dogs was low; therefore, toxic effects from acute human drug over-dosage are unlikely. The single dose safety pharmacology studies showed the expected effects of an anticholinergic drug including mydriasis, increased heart rate and prolonged gastro-intestinal transit time.
The side effects of the repeated dose studies in rats, mice and dogs were related to anticholinergic properties of tiotropium including mydriasis, increased heart rate, constipation, decreased body weight gain, reduced salivary and lacrimal gland secretion. Other relevant changes noted were: mild irritancy of the upper respiratory tract in rats evinced by rhinitis and epithelial changes of the nasal cavity and larynx, and prostatitis along with proteinaceous deposits and lithiasis in the bladder of male rats, increased lung weights in rats and decreased heart weights in dogs.
In the reproduction studies in rabbits and rats harmful effects with respect to pregnancy, embryo/foetal 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.
In a series of in vivo and in vitro mutagenicity assays, tiotropium bromide monohydrate did not cause gene mutations in prokaryotes and in eucaryotes, chromosomal damage in vitro and in vivo conditions or primary DNA damage.
Spiriva Respimat: In juvenile rats exposed from postnatal day 7 to sexual maturity, the same direct and indirect pharmacological changes were observed as in the repeat-dose toxicity studies as well as rhinitis. No systemic toxicity was noted and no toxicologically relevant effects on key developmental parameters, tracheal or key organ development were seen.

Spiriva Handihaler: SPIRIVA is indicated for the maintenance treatment of patients with COPD (including chronic bronchitis and emphysema), the maintenance treatment of associated dyspnoea and for prevention of exacerbations.
Spiriva Respimat: COPD: SPIRIVA RESPIMAT is indicated for the maintenance treatment of patients with COPD (including chronic bronchitis and emphysema), the maintenance treatment of associated dyspnoea, the improvement of COPD compromised quality of life and reduction of exacerbations.
Asthma: SPIRIVA RESPIMAT is indicated as add-on maintenance treatment for the improvement of asthma symptoms, quality of life, and reduction of exacerbations, in patients aged 6 years and older with moderate to severe asthma who remain symptomatic on at least inhaled corticosteroids.

Spiriva Handihaler: The recommended dosage of SPIRIVA is inhalation of the contents of one capsule once daily with the HandiHaler inhalation device at the same time of day (see Instructions for Use under Cautions for Usage).
Special population: Elderly patients can use SPIRIVA at the recommended dose.
Renally impaired patients can use SPIRIVA at the recommended dose. However, as with all predominantly renally excreted drugs, SPIRIVA use should be monitored closely in patients with moderate to severe renal impairment.
Hepatically impaired patients can use SPIRIVA at the recommended dose.
Paediatric population: There is no experience with SPIRIVA in infants and children and therefore should not be used in this age group.
Spiriva Respimat: The recommended dosage of SPIRIVA RESPIMAT is inhalation of the spray of two puffs once daily from the RESPIMAT inhaler at the same time of day (see Instructions for Use under Cautions for Usage).
In the treatment of asthma, the full benefits will be apparent after several doses of SPIRIVA RESPIMAT.
Special populations: Elderly patients can use SPIRIVA RESPIMAT at the recommended dose.
Renally impaired patients can use SPIRIVA RESPIMAT at the recommended dose. However, as with all predominantly renally excreted drugs, SPIRIVA RESPIMAT use should be monitored closely in patients with moderate to severe renal impairment.
Hepatically impaired patients can use SPIRIVA RESPIMAT at the recommended dose.
Paediatric population: COPD does not normally occur in children.
In asthma, the recommended dosage of SPIRIVA RESPIMAT in patients 6 to 17 years of age is inhalation of the spray of two puffs once daily from the RESPIMAT inhaler, at the same time of day (see Instructions for Use under Cautions for Usage).
The efficacy and safety of SPIRIVA RESPIMAT in paediatric patients below 6 year of age with asthma has not yet been established.
Method of Administration: Spiriva Handihaler: SPIRIVA capsules must not be swallowed.

High doses of SPIRIVA/SPIRIVA RESPIMAT may lead to anticholinergic signs and symptoms.
Spiriva Handihaler: However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 micrograms tiotropium in healthy volunteers.
Bilateral conjunctivitis in addition to dry mouth was seen in healthy volunteers following repeated once daily inhalation of 141 micrograms in healthy volunteers, which resolved while still under treatment. In a multiple dose study in COPD patients with a maximum daily dose of 36 micrograms tiotropium over four weeks dry mouth was the only observed adverse event attributable to tiotropium.
Acute intoxication by oral ingestion of tiotropium capsules is unlikely due to low oral bioavailability.
Spiriva Respimat: 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.

SPIRIVA inhalation powder and SPIRIVA RESPIMAT are contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, e.g. ipratropium or oxitropium or to any component of this product (see Precautions).

Spiriva Handihaler: SPIRIVA, as a once daily maintenance bronchodilator, should not be used for the initial treatment of acute episodes of bronchospasm, i.e. rescue therapy.
Spiriva Respimat: SPIRIVA RESPIMAT, as a once daily maintenance bronchodilator, should not be used for the initial treatment of acute episodes of bronchospasm or for the relief of acute symptoms. In the event of an acute attack, a rapid-acting beta-2-agonist should be used.
SPIRIVA RESPIMAT should not be used as a first-line treatment for asthma. Asthma patients must be advised to continue taking anti-inflammatory therapy, i.e. inhaled corticosteroids, unchanged after the introduction of SPIRIVA RESPIMAT, even when their symptoms improve.
Immediate hypersensitivity reactions may occur after administration of SPIRIVA inhalation powder/SPIRIVA RESPIMAT inhalation solution.
As with other anticholinergic drugs, SPIRIVA/SPIRIVA RESPIMAT should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction.
Inhaled medicines may cause inhalation-induced bronchospasm.
As with all predominantly renally excreted drugs, SPIRIVA/SPIRIVA RESPIMAT use should be monitored closely in patients with moderate to severe renal impairment (creatinine clearance of ≤ 50 ml/min).
Patients must be instructed in the correct administration of SPIRIVA capsules/SPIRIVA RESPIMAT. Care must be taken not to allow the powder 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.
SPIRIVA/SPIRIVA RESPIMAT should not be used more frequently than once daily.
SPIRIVA capsules and SPIRIVA cartridges are to be used only with the HandiHaler device and RESPIMAT inhaler, respectively.
Excipients: Spiriva Respimat contains Benzalkonium chloride.
This medicine contains 0.0011 mg benzalkonium chloride in each actuation.
Benzalkonium chloride may cause wheezing and breathing difficulties. Patients with asthma are at an increased risk for these adverse events.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. The occurrence of dizziness or blurred vision may influence the ability to drive and use machinery.

Pregnancy: There is a limited amount of data from the use of tiotropium in pregnant women. Pre-clinical/animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses (see Pharmacology: Toxicology under Actions).
As a precautionary measure, it is preferable to avoid the use of SPIRIVA/SPIRIVA RESPIMAT during pregnancy.
Lactation: Clinical data from nursing women exposed to tiotropium are not available. Based on lactating rodent studies, a small amount of tiotropium is excreted into breast milk.
Therefore, SPIRIVA/SPIRIVA RESPIMAT should not be used in pregnant or nursing women unless the expected benefit outweighs any possible risk to the unborn child or the infant.
Fertility: Clinical data on fertility are not available for tiotropium. A non-clinical study performed with tiotropium showed no indication of any adverse effect on fertility. (see Pharmacology: Toxicology under Actions).

Many of the listed undesirable effects can be assigned to the anticholinergic properties of SPIRIVA/SPIRIVA RESPIMAT.
Adverse drug reactions were identified from data obtained in clinical trials and spontaneous reporting during post approval use of the drug.
Spiriva Handihaler: The clinical trial database includes 9,647 tiotropium patients from 28 placebo-controlled clinical trials with treatment periods ranging between four weeks and four years, contributing 12,469 person years of exposure to tiotropium.

Click on icon to see table/diagram/image

Spiriva Respimat: The clinical trial database for COPD includes 3,282 SPIRIVA RESPIMAT patients from 7 placebo-controlled clinical trials with treatment periods ranging between four weeks and one year, contributing 2,440 person years of exposure.
The clinical trial database for asthma includes 1,930 tiotropium treated patients from 12 placebo controlled trials with treatment period ranging between twelve weeks and one year, contributing 1,128 person years of exposure to tiotropium.
Metabolism and nutrition disorders: dehydration.
Nervous system disorders: dizziness; insomnia.
Eye disorders: glaucoma; intraocular pressure increased; vision blurred.
Cardiac disorders: atrial fibrillation; palpitations; supraventricular tachycardia; tachycardia.
Respiratory, thoracic and mediastinal disorders: cough; epistaxis; pharyngitis; dysphonia; bronchospasm; laryngitis; sinusitis.
Gastrointestinal disorders: dry mouth, usually mild; constipation; oropharyngaeal candidiasis; dysphagia; gastrooesophageal reflux disease; gingivitis; glossitis; stomatitis; intestinal obstruction incl. ileus paralytic.
Skin and subcutaneous tissue disorders, Immune system disorders: rash; pruritus; angioneurotic oedema; urticarial; skin infection and skin ulcer; dry skin; hypersensitivity (including immediate reactions).
Musculoskeletal and connective tissue disorders: joint swelling.
Renal and urinary disorders: urinary retention (usually in men with predisposing factors); dysuria; urinary tract infection.
Paedriatic population: The frequency, type, and severity of adverse reactions in the paediatric population are similar as in adults.

Common concomitant medications (LABA, ICS and their combinations) used by patients with COPD were not found to alter the exposure to tiotropium.
Spiriva Handihaler: 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, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids without clinical evidence of drug interactions.
Limited information about co-administration of other anticholinergic drugs with SPIRIVA is available from two clinical trials: Acute single dose administration of ipratropium bromide with chronically administered SPIRIVA in COPD patients (n=64) and healthy volunteers (n=35) was not associated with an increase in adverse events, changes in vital signs or electrocardiographic findings. However, chronic co-administration of other anticholinergic drugs with SPIRIVA has not been studied and is, therefore, not recommended.
Spiriva Respimat: 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 and asthma, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, antihistamines, mucolytics, leucotriene modifiers, cromones and anti-IgE treatment 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 SPIRIVA RESPIMAT is not recommended.

Instructions for Use/Handling: Spiriva Handihaler: The HandiHaler is an inhalation devise especially designed for inhalation from Spiriva capsules. It must not be used to take any other medication.
Handling Instructions: Remember to carefully follow the doctor's instructions for using SPIRIVA. After first use, the HandiHaler can be used for up to one year to take the medication.
dust cap; mouthpiece; base; piercing button; centre chamber.
1. To release the dust cap press the piercing button completely in and let go.
2. Open the dust cap completely by pulling it upwards.
Then open the mouthpiece by pulling it upwards.
3. Remove a SPIRIVA capsule from the blister (only immediately before use) and place it in the centre chamber. It does not matter which way the capsule is placed in the chamber.
4. Close the mouthpiece firmly until a click is heard, leaving the dust cap open.
5. Hold the HandiHaler device with the mouthpiece upwards and press the piercing button completely in only once, and release.
This makes holes in the capsule and allows the medication to be released when the patient breathes in.
6. Breathe out completely.
Important: Avoid breathing into the mouthpiece at any time.
7. Raise the HandiHaler to the mouth and close the lips tightly around the mouthpiece. Keep the head in an upright position and breathe in slowly and deeply but at a rate sufficient to hear or feel the capsule vibrate.
Breathe in until the lungs are full; then hold breath as long as comfortable and at the same time take the HandiHaler out of the mouth. Resume normal breathing.
Repeat steps 6 and 7 once, in order to empty the capsule completely.
8. Open the mouthpiece again. Tip out the used capsule and dispose.
Close the mouthpiece and dust cap for storage of the HandiHaler device.
Cleaning the HandiHaler: Clean the HandiHaler once a month.
Open the dust cap and mouthpiece. Then open the base by lifting the piercing button. Rinse the complete inhaler with warm water to remove any powder. Dry the HandiHaler thoroughly by tipping excess water out onto a paper towel and air-dry afterwards, leaving the dust cap, mouthpiece and base open. It takes 24 hours to air dry, so clean it immediately after use so that it will be ready for the next dose. The outside of the mouthpiece may be cleaned with a moist but not wet tissue if needed.
Blister handling: A. Separate the blister strips by tearing along the perforation.
B. Peel back foil (only immediately before use) using the tab until one capsule is fully visible. After first opening of the blister, use within 9 days.
In case a second capsule is exposed to air inadvertently this capsule has to be discarded.
C. Remove capsule.
SPIRIVA capsules contain only a small amount of powder so that the capsule is only partially filled.
Spiriva Respimat: Read these Instructions for Use before using SPIRIVA RESPIMAT.
Children should use SPIRIVA RESPIMAT with an adult's assistance.
Use this inhaler only ONCE A DAY. Each time it will be used, take TWO PUFFS.
If not been used for more than 7 days release one puff towards the ground.
If not been used for more than 21 days repeat steps 4 to 6 until a cloud is visible. Then repeat steps 4 to 6 three more times.
How to care for SPIRIVA 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 SPIRIVA RESPIMAT inhaler performance.
When to get a new SPIRIVA RESPIMAT: The SPIRIVA 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 SPIRIVA 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 SPIRIVA 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.
Close the cap until the next use of the inhaler.

Spiriva Handihaler: Do not store above 25^oC.
Spiriva Respimat: Do not freeze.
Do not store above 30°C.

Antiasthmatic & COPD Preparations

R03BB04 - tiotropium bromide ; Belongs to the class of other inhalants used in the treatment of obstructive airway diseases, anticholinergics.

D