Spiriva

Tiotropium bromide.

Spiriva: Light green hard capsules with the product code TI 01 and company logo printed on the capsule.
Each capsule contains 22.5 microgram tiotropium bromide monohydrate equivalent to 18 microgram tiotropium.
The delivered dose (the dose that leaves the mouthpiece of the HandiHaler device) is 10 microgram tiotropium.
Spiriva Respimat: SPIRIVA RESPIMAT cartridges contain a clear, colourless, solution for inhalation filled into a plastic container which is inside an aluminium cylinder (cartridge) for use with the RESPIMAT inhaler. SPIRIVA RESPIMAT is for oral inhalation only.
Each pack consists of one RESPIMAT inhaler and one cartridge, delivering 60 metered puffs. Each puff contains tiotropium 2.5 micrograms, equivalent to tiotropium bromide monohydrate 3.1 micrograms.
Active ingredient: tiotropium (as tiotropium bromide monohydrate).
Chemical name: 3-Oxa-9-azoniatricyclo[3.3.1.0^2,4]nonane, 7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-, bromide, monohydrate, (1α, 2β, 4β, 5α, 7β)-.
Molecular formula: C₁₉H₂₂NO₄S₂Br.H₂O.
Molecular weight: 490.4 (monohydrate).
CAS number: 139404-48-1.
Tiotropium bromide is a white to yellowish-white, odourless crystalline powder. It exists as a quaternary ammonium salt, and there are no ionisable functional groups on the molecule. The active substance is not optically active.
Tiotropium bromide is freely soluble in dimethyl sulphoxide, soluble in methanol, sparingly soluble in water and practically insoluble in methylene chloride. The solubility in aqueous solutions at room temperature is approx. 2.5%, independent of pH. At pH 7.4, the apparent partition coefficient (log P_app) is -2.25.
A monohydrate form of tiotropium bromide is produced by the synthetic process. The compound melts with decomposition between 225°C and 235°C, when determined by differential scanning calorimetry at a heating rate of 10 K per minute.
Excipients/Inactive Ingredients: Spiriva: Lactose monohydrate (which contains milk protein).
Spiriva Respimat: Benzalkonium chloride, disodium edetate, purified water, and hydrochloric acid for pH adjustment.

Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, anticholinergics. ATC code: R03B B04.
Pharmacology: Spiriva Respimat: Tiotropium is a long-acting, specific antimuscarinic (anticholinergic) agent. It has similar affinity to the muscarinic receptor subtypes M₁ to M₅ (K_D 5-41 pM). In the airways, inhibition by tiotropium 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. In non-clinical in vitro as well as in vivo studies, bronchoprotective effects were dose-dependent. Bronchoprotective effects lasting at least 24 hours were observed in some of the in vivo studies. The long duration of effect of tiotropium is likely to be due to its slow dissociation from M₃-receptors. Tiotropium exhibited a significantly longer dissociation half-life from M₃ receptors than ipratropium.
Tiotropium, a N-quaternary anticholinergic agent, is topically (broncho-) selective when administered by inhalation. The high potency (IC₅₀ approximately 0.4 nM for M₃) and slow receptor dissociation is associated with a significant and long-acting bronchodilation in patients with chronic obstructive pulmonary disease (COPD) and asthma.
The bronchodilation following inhalation of tiotropium is primarily a local effect on the airways, not a systemic one.
Pharmacodynamics: Spiriva: Mechanism of action: Tiotropium bromide is a long-acting, specific, muscarinic receptor antagonist, in clinical medicine often called an anticholinergic. By binding to the muscarinic receptors in the bronchial smooth musculature, tiotropium bromide inhibits the cholinergic (bronchoconstrictive) effects of acetylcholine, released from parasympathetic nerve endings. It has similar affinity to the subtypes of muscarinic receptors, M₁ to M₅. In the airways, tiotropium bromide competitively and reversibly antagonises the M₃ receptors, resulting in relaxation. The effect was dose dependent and lasted longer than 24h. The long duration is probably due to the very slow dissociation from the M₃ receptor, exhibiting a significantly longer dissociation half-life than ipratropium. As an N-quaternary anticholinergic, tiotropium bromide is topically (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic range before systemic anticholinergic effects may occur.
Pharmacodynamic effects: The bronchodilation is primarily a local effect (on the airways), not a systemic one. 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.
Cardiac electrophysiology: 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 significantly prolong QT intervals of the ECG.
Clinical efficacy and safety: The clinical development programme included four one-year and two six-month randomised, double-blind studies in 2,663 patients (1,308 receiving tiotropium bromide). The one-year programme consisted of two placebo-controlled trials and two trials with an active control (ipratropium). The two six-month trials were both, salmeterol and placebo controlled. These studies included lung function and health outcome measures of dyspnoea, exacerbations and health-related quality of life.
Lung function: Tiotropium bromide, 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 which was maintained for 24 hours. Pharmacodynamic steady state was reached within one week with the majority of bronchodilation observed by the third day. Tiotropium bromide significantly improved morning and evening PEFR (peak expiratory flow rate) as measured by patient's daily recordings. The bronchodilator effects of tiotropium bromide were maintained throughout the one-year period of administration with no evidence of tolerance.
A randomised, placebo-controlled clinical study in 105 COPD patients demonstrated that bronchodilation was maintained throughout the 24 hour dosing interval in comparison to placebo regardless of whether the drug was administered in the morning or in the evening.
Long-term clinical trials (6 months and 1 year): Dyspnoea, Exercise tolerance: Tiotropium bromide significantly improved dyspnoea (as evaluated using the Transition Dyspnoea Index.). This improvement was maintained throughout the treatment period.
The impact of improvements in dyspnoea on exercise tolerance was investigated in two randomised, double-blind, placebo-controlled trials in 433 patients with moderate to severe COPD. In these trials, six weeks of treatment with SPIRIVA significantly improved symptom-limited exercise endurance time during cycle ergometry at 75% of maximal work capacity by 19.7% (Trial A) and 28.3% (Trial B) compared with placebo.
Health-related Quality of Life: In a 9-month, randomized, double-blind, placebo-controlled clinical trial of 492 patients, SPIRIVA improved health-related quality of life as determined by the St. George's Respiratory Questionnaire (SGRQ) total score. The proportion of patients treated with SPIRIVA which achieved a meaningful improvement in the SGRQ total score (i.e. > 4 units) was 10.9% higher compared with placebo (59.1% in the SPIRIVA groups vs. 48.2% in the placebo group (p=0.029). The mean difference between the groups was 4.19 units (p=0.001; confidence interval: 1.69-6.68). The improvements of the subdomains of the SGRQ-score were 8.19 units for "symptoms", 3.91 units for "activity" and 3.61 units for "impact on daily life". The improvements of all of these separate subdomains were statistically significant.
COPD Exacerbations: In a randomized, double-blind, placebo controlled trial of 1,829 patients with moderate to very severe COPD, tiotropium bromide statistically significantly reduced the proportion of patients who experienced exacerbations of COPD (32.2% to 27.8%) and statistically significantly reduced the number of exacerbations by 19% (1.05 to 0.85 events per patient year of exposure). In addition, 7.0% of patients in the tiotropium bromide group and 9.5% of patients in the placebo group were hospitalized due to a COPD exacerbation (p=0.056). The number of hospitalizations due to COPD was reduced by 30% (0.25 to 0.18 events per patient year of exposure).
A one-year randomised, double-blind, double-dummy, parallel-group trial compared the effect of treatment with 18 microgram of SPIRIVA once daily with that of 50 microgram 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 Table 1.)

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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).
Long-term clinical trials (more than 1 year, up to 4 years): In a 4-year, randomised, double-blind, placebo-controlled clinical trial of 5,993 randomised patients (3,006 receiving placebo and 2,987 receiving SPIRIVA), the improvement in FEV₁ resulting from SPIRIVA, compared with placebo, remained constant throughout 4 years. A higher proportion of patients completed ≥ 45 months of treatment in the SPIRIVA group compared with the placebo group (63.8% vs. 55.4%, p<0.001). The annualized rate of decline of FEV₁ compared to placebo was similar between SPIRIVA and placebo. 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 (as recorded through adverse event reporting) by 19% (2.09 vs. 1.68 cases per 100 patient years, relative risk (tiotropium/placebo) = 0.81, 95% CI = 0.65, 0.999).
Tiotropium active-controlled study: A long-term, large scale randomised, double-blind, active-controlled study with an observation period up to 3 years has been performed to compare the efficacy and safety of SPIRIVA HandiHaler and SPIRIVA RESPIMAT (5,694 patients receiving SPIRIVA HandiHaler; 5,711 patients receiving SPIRIVA RESPIMAT). 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 numerically similar during the study with SPIRIVA HandiHaler and SPIRIVA RESPIMAT (hazard ratio (SPIRIVA HandiHaler/SPIRIVA RESPIMAT) 1.02 with a 95% CI of 0.97 to 1.08). The median number of days to the first COPD exacerbation was 719 days for SPIRIVA HandiHaler and 756 days for SPIRIVA RESPIMAT.
The bronchodilator effect of SPIRIVA HandiHaler was sustained over 120 weeks, and was similar to SPIRIVA RESPIMAT. The mean difference in trough FEV₁ for SPIRIVA HandiHaler versus SPIRIVA RESPIMAT was 0.010 L (95% CI -0.018 to 0.038 L).
In the post-marketing TIOSPIR study comparing SPIRIVA RESPIMAT and SPIRIVA HandiHaler, all-cause mortality including vital status follow up was similar during the study with SPIRIVA HandiHaler and SPIRIVA RESPIMAT (hazard ratio (SPIRIVA HandiHaler/SPIRIVA RESPIMAT) 1.04 with a 95% CI of 0.91 to 1.19).
Pediatric population: No data in paediatric population were established (see Dosage & Administration).
Spiriva Respimat: Clinical Trials: COPD: The clinical Phase III programme for COPD included two 1-year, two 12-week and two 4-week randomised, double-blind studies in 2901 patients with COPD (1038 receiving the 5 micrograms 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, with trough FEV₁ (i.e. FEV₁ measured approximately 10 minutes before the final dose) as the primary endpoint. In addition, the two 1-year studies included health outcome measures of health-related quality of life, dyspnoea, and effect on exacerbations as co-primary endpoints.
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.
Mean trough FEV₁ treatment difference for SPIRIVA RESPIMAT over placebo in the combined 1-year trials at day 337 was 127 mL (p<0.0001 vs. placebo). Improvement of lung function was maintained for 24 hours at steady state. Pharmacodynamic steady state was reached within one week. The bronchodilator effects of SPIRIVA RESPIMAT were maintained throughout the 48-week period of administration with no evidence of tolerance.
Mean trough FEV₁ treatment differences for the combined 12-week trials at day 85 was 118 mL for SPIRIVA RESPIMAT over placebo (p<0.0001) and 64 mL for SPIRIVA RESPIMAT over ipratropium bromide (p=0.0060).
A combined analysis of two randomised, placebo-controlled, crossover, clinical studies demonstrated that the bronchodilator response as measured by mean trough FEV₁ for SPIRIVA RESPIMAT was 29 mL higher than Spiriva HandiHaler (18 micrograms) inhalation powder after a 4-week treatment period (p=0.03). Since steady state efficacy is reached within 4 weeks, no longer term study comparing the two products has been conducted.
SPIRIVA RESPIMAT significantly improved morning and evening PEFR (peak expiratory flow rate) as measured by patient's daily recordings (morning improvement mean 22 L/min, p<0.0001; evening improvement mean 26 L/min, p<0.0001). The use of SPIRIVA RESPIMAT resulted in a reduction of rescue bronchodilator use compared to placebo.
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) the magnitude of change being 1.05 units at day 337 (p<0.0001 vs. placebo). The mean Baseline Dyspnoea Index was 6.41 units. 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. By day 337 the mean treatment difference improvement in SGRQ total score from placebo (pooled data from the two 1-year studies) was 3.5 for SPIRIVA RESPIMAT (p<0.0001 vs. placebo). The mean SGRQ total score at baseline was 44.8.
(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.)

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Long-term tiotropium active- controlled study: A long term, large scale, randomised, double-blind, active-controlled study with an observation 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 (2 puffs comprise one medicinal dose of 5 micrograms); 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 L).
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 48 week, 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, tiotropium 5 microgram, once daily) 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 48-week 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 1).

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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 48-week period of administration with no evidence of tachyphylaxis or tolerance (see Figure 2).

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

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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 (treatment difference: 0.117, 95% CI: 0.011, 0.223, p=0.0312).
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).

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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) was based on the following clinical trials and a partial extrapolation of data from adults: 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, tiotropium 5 microgram, once daily).
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 tiotropium 5 microgram, once daily).
Children (1-5 years): one 12-week randomised, double-blind placebo-controlled study in a total of 101 asthma patients (31 receiving SPIRIVA RESPIMAT tiotropium 5 microgram, once daily).
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 with moderate asthma 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 4).

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In the 12-week PensieTinA-asthma study in patients with severe asthma who were symptomatic on maintenance treatment of at least medium dose ICS in combination with 1 or more controller medication (e.g. LABA), 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 with moderate asthma 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 0.164 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 5).

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In the 12-week VivaTinA-asthma study in patients with severe asthma who were symptomatic on maintenance treatment of at least medium dose ICS in combination with 1 or more controller medication (e.g. LABA), 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.
Pharmacokinetics: Spiriva: General Introduction: Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium bromide 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 as follows were obtained with higher doses than recommended for therapy.
General Characteristics of the Active Substance after Administration of the Medicinal Product: Absorption: 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%.
Maximum tiotropium plasma concentrations were observed 5-7 minutes after inhalation. At steady state, peak tiotropium plasma levels 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. Systemic exposure following the inhalation of tiotropium via the HandiHaler device was similar to tiotropium inhaled via the Respimat inhaler.
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 bromide 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. The ester tiotropium bromide is nonenzymatically cleaved to the alcohol (N-methylscopine) and acid compound (dithienylglycolic acid) that are inactive on 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 (CYP) dependent oxidation and subsequent glutathion conjugation to a variety of Phase II-metabolites.
In vitro studies in liver microsomes reveal that the enzymatic pathway can be inhibited by the CYP 2D6 (and 3A4) inhibitors, quinidine, ketoconazole and gestodene. Thus CYP 2D6 and 3A4 are involved in metabolic pathway that is responsible for the elimination of a smaller part of the dose. Tiotropium bromide even in supra-therapeutic concentrations does not inhibit CYP 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.
Elimination: The effective half-life of tiotropium ranges between 27-45 h in COPD patients. Total clearance was 880 ml/min after an intravenous dose in young healthy volunteers. Intravenously administered tiotropium is mainly excreted unchanged in urine (74%). After dry powder inhalation by COPD patients to steady-state, urinary excretion is 7% (1.3 μg) of the unchanged drug 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.
Characteristics in Patients: Geriatric 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, mild renal impairment (CL_CR 50-80 ml/min) resulted in slightly higher AUC_0-6,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 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.
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.
Japanese COPD Patients: In cross trial comparison, mean peak tiotropium plasma concentrations 10 minutes post-dosing at steady-state were 20% to 70% higher in Japanese compared to Caucasian COPD patients following inhalation of tiotropium but there was no signal for higher mortality or cardiac risk in Japanese patients compared to Caucasian patients. Insufficient pharmacokinetic data is available for other ethnicities or races.
Paediatric Patients: See Dosage & Administration.
Pharmacokinetic / Pharmacodynamic Relationship(s): There is no direct relationship between pharmacokinetics and pharmacodynamics.
Spiriva Respimat: Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium bromide is available as solution for inhalation administered by the RESPIMAT inhaler. Generally with the inhaled route of administration, the majority of the delivered dose is swallowed and deposited in the gastrointestinal tract, and to a lesser extent is delivered to the lungs. Approximately 40% of the inhaled dose of tiotropium RESPIMAT is deposited in the lungs, the target organ, the remaining amount being deposited in the gastrointestinal tract. Some of the tiotropium RESPIMAT pharmacokinetic data described as follows were obtained with higher doses than recommended for therapy.
Bioequivalence: The primary objective of the Phase II, crossover study 205.458 involving 123 patients with COPD was to compare the pharmacokinetics of 5 μg tiotropium solution for inhalation delivered by the RESPIMAT Inhaler (Tio R 5) with tiotropium powder for inhalation 18 μg delivered by the HandiHaler (Tio HH 18). The exposure to tiotropium following the use of Tio R 5 was lower compared to Tio HH 18. Using the parameters AUC_0‐6,ss and C_max,ss, bioequivalence was not established between Tio R 5 and Tio HH 18. The ratio of AUC_0‐6,ss (Tio R 5/ Tio HH 18) was 75.99% (90% confidence interval of (70.44, 81.98)). The ratio of C_max,ss was 80.66% (90% CI: 73.49, 88.52).
Absorption: Following inhalation by young healthy volunteers, urinary excretion data suggests that approximately 33% of the inhaled dose reaches the systemic circulation. It is expected from the chemical structure of the compound that tiotropium is poorly absorbed from the gastro-intestinal tract. This was confirmed in a study in young healthy volunteers, with a low bioavailability of 2-3% for oral solutions. 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 patients with COPD 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: The drug 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.
Metabolism: Metabolism does not occur to any great extent in young healthy volunteers, as indicated by 74% renal excretion of unchanged drug after an intravenous dose. The major metabolic pathway is non-enzymatic ester cleavage to the alcohol N-methylscopine and dithienylglycolic acid that are inactive on muscarinic receptors.
In vitro metabolism: In studies in animals and in vitro experiments with human liver microsomes and hepatocytes, minor amounts of a variety of glutathione conjugates, after oxidation of the thiophene rings, were observed.
In vitro studies in human liver microsomes revealed that the enzymatic pathway, relevant for only a small amount of tiotropium metabolism, can be inhibited by cytochrome P450 (CYP) 2D6 inhibitor quinidine and CYP 3A4 inhibitors ketoconazole and gestodene.
Tiotropium, even in supra-therapeutic concentrations, does not inhibit CYP 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.
Excretion: The effective half-life of tiotropium ranges between 27 to 45 h following inhalation by patients with COPD or asthma.
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. Urinary excretion of unchanged substance in young healthy volunteers is 74% of an intravenous dose. After inhalation of the solution for inhalation by patients with COPD, 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.
The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine. After chronic, once daily inhalation, pharmacokinetic steady state was reached by day 7, with no accumulation thereafter.
Tiotropium demonstrates linear pharmacokinetics in the therapeutic range, independent of the formulation.
Special populations: 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 patients with COPD <65 years to 275 mL/min in patients with COPD ≥ 65 years. This did not result in a corresponding increase in AUC_0-6,ss and 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 (n=3), the total exposure as measured by urinary excretion (over 3 hours) 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 to patients with COPD 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 COPD patients with normal renal function (CL_CR >80 mL/min. In patients with COPD with moderate to severe renal impairment (CL_CR <50 mL/min), the intravenous administration of tiotropium resulted in a doubling of the total exposure (82% higher AUC_0-4h and 52% higher C_max) compared to patients with COPD 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: There are no data on the pharmacokinetics of tiotropium in hepatic impairment. 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.
Toxicology: Spiriva: Preclinical safety data: Many effects observed in conventional studies of safety pharmacology, repeated dose toxicity, and reproductive toxicity could be explained by the anticholinergic properties of tiotropium bromide. Typically in animals reduced food consumption, inhibited body weight gain, dry mouth and nose, reduced lacrimation and salivation, mydriasis and increased heart rate were observed. Other relevant effects noted in repeated dose toxicity studies were: mild irritancy of the respiratory tract in rats and mice evinced by rhinitis and epithelial changes of the nasal cavity and larynx, and prostatitis along with proteinaceous deposits and lithiasis in the bladder in rats.
Harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development could only be demonstrated at maternally toxic dose levels. Tiotropium bromide was not teratogenic in rats or rabbits. 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.
The respiratory (irritation) and urogenital (prostatitis) changes and reproductive toxicity were observed at local or systemic exposures more than five-fold the therapeutic exposure. Studies on genotoxicity and carcinogenic potential revealed no special hazard for humans.

Spiriva: 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 long term maintenance treatment of bronchospasm and dyspnoea associated with chronic obstructive pulmonary disease (COPD). SPIRIVA RESPIMAT is indicated for the reduction of COPD exacerbations.
Asthma: SPIRIVA RESPIMAT is indicated as add-on maintenance bronchodilator treatment in patients aged 6 years and older with severe asthma.

Spiriva: Posology: The recommended dosage of SPIRIVA is inhalation of the contents of one capsule once daily with the HANDIHALER device at the same time of day (see Instructions for use under Cautions for Usage).
SPIRIVA should only be inhaled with the HandiHaler device.
The recommended dose should not be exceeded.
SPIRIVA capsules must not be swallowed.
Special populations: Geriatric patients can use tiotropium bromide at the recommended dose.
Renally impaired patients can use tiotropium bromide at the recommended dose. For patients with moderate to severe impairment (creatinine clearance ≤ 50 ml/min) see Precautions and Pharmacology: Pharmacokinetics under Actions.
Hepatically impaired patients can use tiotropium bromide at the recommended dose (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: COPD: There is no relevant use in the paediatric population (below 18 years) in the indication stated under Indications/Uses.
Cystic fibrosis: The safety and efficacy of SPIRIVA 18 microgram in children and adolescents has not been established. No data are available.
Method of administration: To ensure proper administration of the medicinal product the patient should be trained how to use the inhaler by the physician or by other healthcare professionals.
Spiriva Respimat: The recommended dosage of tiotropium using the SPIRIVA RESPIMAT is 5 micrograms. This is administered as two puffs once daily at the same time each day (see RESPIMAT inhaler Instructions for Use).
The recommended dose should not be exceeded.
In the treatment of asthma, the full benefits will be apparent after several doses of SPIRIVA RESPIMAT.
Paediatric population: In asthma, the recommended dosage of tiotropium using the SPIRIVA RESPIMAT in patients 6 to 17 years of age is 5 micrograms. This is administered as two puffs once daily from the RESPIMAT inhaler, at the same time each day (see SPIRIVA RESPIMAT Instructions for Use under Cautions for Usage).
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.

High doses of tiotropium bromide may lead to anticholinergic signs and symptoms.
However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 340 microgram tiotropium bromide for Spiriva and 282 micrograms tiotropium for Spiriva Respimat in healthy volunteers. Additionally, no relevant adverse effects, beyond dry mouth, were observed following 7 day dosing of up to 170 microgram tiotropium bromide for Spiriva and up to 141 micrograms tiotropium for Spiriva Respimat in healthy volunteers. In a multiple dose study in COPD patients with a maximum daily dose of 43 microgram tiotropium bromide for Spiriva and 36 micrograms tiotrpium for Spiriva Respimat over four weeks no significant undesirable effects have been observed.
Spiriva: Acute intoxication by inadvertent oral ingestion of tiotropium bromide capsules is unlikely due to low oral bioavailability.
Spiriva Respimat: No relevant adverse events, beyond dry mouth/throat and dry nasal mucosa, were observed following 14-day dosing of up to 40 micrograms tiotropium solution for inhalation 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 patients with COPD when a daily dose of 10 micrograms tiotropium solution for inhalation was given over 4-48 weeks.

SPIRIVA/SPIRIVA RESPIMAT is contraindicated in patients with a history of hypersensitivity to tiotropium bromide, atropine or its derivatives, e.g. ipratropium or oxitropium or to any other component of this product (see list of excipients in Description).
Spiriva: Tiotropium bromide inhalation powder is contraindicated in patients with a hypersensitivity to the excipient lactose monohydrate which contains milk protein.

Immediate hypersensitivity reactions may occur after administration of SPIRIVA/SPIRIVA RESPIMAT.
Dry mouth, which has been observed with anticholinergic treatment, may in the long term be associated with dental caries.
Inhaled medicines may cause inhalation-induced bronchospasm.
Tiotropium should be used with caution in patients with recent myocardial infarction < 6 months; any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy in the past year; hospitalisation of heart failure (NYHA Class III or IV) within the past year. These patients were excluded from the clinical trials and these conditions may be affected by the anticholinergic mechanism of action.
SPIRIVA/SPIRIVA RESPIMAT should not be used more frequently than once daily (see Overdosage).
Effects on ability to drive or operate machinery: No studies on the effects on the ability to drive and use machines have been performed. The occurrence of dizziness, blurred vision, or headache may influence the ability to drive and use machinery.
Spiriva: Tiotropium bromide, as a once daily maintenance bronchodilator, should not be used for the initial treatment of acute episodes of bronchospasm, i.e. rescue therapy.
Consistent with its anticholinergic activity, tiotropium bromide should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction (see Adverse Reactions).
As plasma concentration increases with decreased renal function in patients with moderate to severe renal impairment (creatinine clearance ≤ 50 ml/min) tiotropium bromide should be used only if the expected benefit outweighs the potential risk. There is no long term experience in patients with severe renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Patients should be cautioned to avoid getting the drug powder into their eyes. They should be advised that this may result in precipitation or worsening of narrow-angle glaucoma, eye pain or discomfort, temporary blurring of vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema. Should any combination of these eye symptoms develop, patients should stop using tiotropium bromide and consult a specialist immediately.
SPIRIVA capsules contain 5.5 mg lactose monohydrate.
Spiriva Respimat: SPIRIVA RESPIMAT, as a once daily maintenance bronchodilator, should not be used for the 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. Patients with asthma 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.
As with other anticholinergic drugs, SPIRIVA 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, SPIRIVA was associated with a non-significant increase in the risk of urinary retention, and a significant increase in the risk of micturition difficulties.
As with all predominantly renally excreted drugs, SPIRIVA use should be monitored closely in patients with moderate to severe renal impairment (creatinine clearance of ≤ 50 mL/min) (see Pharmacology: Pharmacokinetics under Actions). There is no long term experience in patients with severe renal impairment.
Patients must be instructed in the correct administration of SPIRIVA. 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.
SPIRIVA cartridges are to be used only with RESPIMAT inhaler (see SPIRIVA RESPIMAT Instructions for Use under Cautions for Usage).
Effects on fertility: Clinical data on fertility are not available for tiotropium. Tiotropium (as bromide) did not affect the fertility of male or female rats when administered by inhalation at doses up to 2 mg/kg (750x the maximum recommended human daily dose of the drug, based on body surface area).
Genotoxicity: Tiotropium (as bromide) did not exhibit any genotoxic effects in assays for gene mutation (bacteria and mammalian cells in vitro and in vivo mouse micronucleus test) or DNA damage (rat hepatocytes in vitro).
Carcinogenicity: Long-term carcinogenicity studies in mice and rats, with tiotropium (as bromide) administered by inhalation, showed no evidence of neoplastic responses. The highest doses studied were approximately 0.8x (male mouse), 38x (female mouse) and 16x (rat) greater than the maximum recommended human daily dose of the drug, based on body surface area.
Hepatic Impairment: There are no data on the use of tiotropium in patients with hepatic impairment. As tiotropium is primarily cleared by renal mechanisms, no dosage adjustment is recommended. However patients should be monitored closely.
Renal Impairment: 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 COPD and asthma patients with moderate to severe renal impairment (creatinine clearance ≤ 50 mL/min).
Use in Pregnancy: (Category B1): See Use in Pregnancy & Lactation.
Use in Lactation: See Use in Pregnancy & Lactation.
Use in Children: COPD does not normally occur in children.
In children aged 1-5 years: One 12-week clinical study was conducted in a total of 101 children with asthma on background treatment of at least ICS.
An Aerochamber Plus Flow-Vu valved holding chamber with facemask was used to administer trial medication in 98 patients.
The primary objective of the study was safety; efficacy assessments were exploratory.
There was no difference in the exploratory symptoms score in those treated with tiotropium versus placebo. The number of asthma adverse events was lower for SPIRIVA RESPIMAT compared to placebo.
Tiotropium has not been studied in children less than 1 year.
Use in the Elderly: Elderly patients can use SPIRIVA RESPIMAT at the recommended dose. Renal clearance of tiotropium is likely to be slower in elderly patients (see Renal Impairment as previously mentioned).

Spiriva: Pregnancy: There is a very limited amount of data from the use of tiotropium in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses (see Pharmacology: Toxicology: Preclinical safety data under Actions). As a precautionary measure, it is preferable to avoid the use of SPIRIVA during pregnancy.
Breast-feeding: It is unknown whether tiotropium bromide is excreted in human breast milk. Despite studies in rodents which have demonstrated that excretion of tiotropium bromide in breast milk occurs only in small amounts, use of SPIRIVA is not recommended during breast-feeding. Tiotropium bromide is a long-acting compound. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with SPIRIVA should be made taking into account the benefit of breast-feeding to the child and the benefit of SPIRIVA therapy to the woman.
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: Preclinical safety data under Actions).
Spiriva Respimat: Use in Pregnancy: (Category B1): There is a limited amount of data from the use of tiotropium in pregnant women. Reproductive toxicity studies with tiotropium bromide administered by inhalation to rats and rabbits at doses up to 2.0 and 0.5 mg/kg/day, respectively, produced no evidence of fetal malformations. These doses correspond to 750x and 400x the maximum recommended human daily dose of the drug based on body surface area. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses.
As a precautionary measure, it is preferable to avoid the use of SPIRIVA RESPIMAT during pregnancy.
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.
Use in Lactation: Clinical data from lactating women exposed to tiotropium are not available. Based on studies in lactating rats, a small amount of tiotropium is excreted in breast milk.
Therefore, SPIRIVA RESPIMAT should not be used in lactating women unless the expected benefit outweighs any possible risk to the infant.

Summary of the safety profile: Many of the listed undesirable effects can be assigned to the anticholinergic properties of SPIRIVA/SPIRIVA RESPIMAT.
Spiriva: Tabulated summary of adverse reactions: The frequencies assigned to the undesirable effects listed as follows are based on crude incidence rates of adverse drug reactions (i.e. events attributed to tiotropium) observed in the tiotropium group (9,647 patients) from 28 pooled placebo-controlled clinical trials with treatment periods ranging from four weeks to four years.
Frequency is defined using the following convention: 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); very rare (<1/10,000), not known (cannot be estimated from the available data). (See Table 5.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: In controlled clinical studies, the commonly observed undesirable effects were anticholinergic undesirable effects such as dry mouth which occurred in approximately 4% of patients. In 28 clinical trials, dry mouth led to discontinuation in 18 of 9,647 tiotropium treated patients (0.2 %).
Serious undesirable effects consistent with anticholinergic effects include glaucoma, constipation and intestinal obstruction including ileus paralytic as well as urinary retention.
Other special population: An increase in anticholinergic effects may occur with increasing age.
Spiriva Respimat: Many of the listed adverse effects can be assigned to the anticholinergic properties of SPIRIVA RESPIMAT.
Adverse drug reactions were identified from data obtained in clinical trials and spontaneous reporting during post approval use of the drug.
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.
Frequency is defined using the following convention: 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); very rare (<1/10,000), not known (cannot be estimated from the available data). (See Table 6.)

Click on icon to see table/diagram/image

Description of selected adverse effects: In controlled clinical studies of COPD, the commonly observed adverse effects were anticholinergic undesirable effects such as dry mouth which occurred in approximately 2.9% of patients. In asthma the incidence of dry mouth was 0.83%.
Serious adverse effects consistent with anticholinergic effects include glaucoma, constipation, intestinal obstruction (including paralytic ileus) and urinary retention.
An increase in anticholinergic effects may occur with increasing age.
Paedriatic population: The frequency, type, and severity of adverse reactions in the paediatric population are similar as in adults.

Spiriva: Although no formal drug interaction studies have been performed, tiotropium bromide inhalation powder has been used concomitantly with other drugs without clinical evidence of drug interactions. These include sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, commonly used in the treatment of COPD.
Use of LABA or ICS was not found to alter the exposure to tiotropium.
The co-administration of tiotropium bromide with other anticholinergic-containing drugs 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 which are 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.
Common concomitant medications (LABA, ICS and their combinations) used by patients with COPD were not found to alter the exposure to tiotropium.
Limited information about co-administration of other anticholinergic medicines with SPIRIVA is available from a clinical trial. The concomitant use of SPIRIVA RESPIMAT with other anticholinergic agents (e.g. glycopyrronium, aclidinium, umeclidinium, ipratropium) is expected to have additive anticholinergic effects. Acute single dose administration of ipratropium bromide after 19 days of SPIRIVA treatment in healthy volunteers (n=35) was not associated with relevant changes in vital signs or electrocardiographic findings. Adverse events were reported by 3 (9%) of subjects in the study during ipratropium treatment with tiotropium compared to 1 (3%) during placebo treatment with tiotropium. Ipratropium was associated with a 16% decrease in salivary secretions in healthy volunteers. The chronic co- administration of tiotropium bromide with other anticholinergic medicines has not been studied. Therefore, the chronic co-administration of other anticholinergic drugs with SPIRIVA RESPIMAT is not recommended.

Instructions for Use: Spiriva HandiHaler: Remember to carefully follow the doctor's instructions for using SPIRIVA. The HandiHaler is especially designed for SPIRIVA. It must not be used to take any other medication. HandiHaler can be used for up to one year to take the medication.
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, see blister handling) 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: Please 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 the 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 of water out on 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 right after the patient used it and it will be ready for the next dose. If needed, the outside of the mouthpiece may be cleaned with a moist but not wet tissue.
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.
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: Introduction: Read these Instructions for Use before the patient starts using SPIRIVA RESPIMAT (tiotropium bromide monohydrate).
Children should use SPIRIVA RESPIMAT with an adult's assistance.
The patient will need to use this inhaler only ONCE A DAY. Each time the patient uses it, take TWO PUFFS.
How to store SPIRIVA RESPIMAT: Keep SPIRIVA RESPIMAT out of the sight and reach of children.
Do not freeze SPIRIVA RESPIMAT.
If SPIRIVA RESPIMAT has not been used for more than 7 days release one puff towards the ground.
If SPIRIVA 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.
Do not use SPIRIVA RESPIMAT after the expiry date.
Do not touch the piercing element inside the clear base.
How to care for the 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: 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, 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 the breath for 10 seconds or for as long as comfortable.
Repeat Turn, Open, Press for a total of 2 puffs.
Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Antiasthmatic & COPD Preparations

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

P₁S₁S₃