Spiriva/Spiriva Respimat

Spiriva/Spiriva Respimat

tiotropium bromide

Manufacturer:

Boehringer Ingelheim

Distributor:

Metro Drug
Full Prescribing Info
Contents
Tiotropium bromide.
Description
Spiriva: Each capsule for inhalation contains tiotropium as bromide monohydrate 18 mcg.
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).
Tiotropium bromide (Spiriva Respimat) solution for inhalation is a clear, colourless solution of tiotropium bromide monohydrate filled into a 4.5 mL cartridge. Each cartridge contains 30 labeled doses.
The solution is to be used with a Respimat Inhaler. Each actuation of the Respimat Inhaler delivers 2.5 μg tiotropium from the mouthpiece. One dose of 5 μg tiotropium consists of two actuations.
Excipients: Benzalkonium chloride, Disodium edetate, Purified water, Hydrochloric acid for pH adjustment.
Action
Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, anticholinergics. ATC code: R03B B04.
Pharmacology: Pharmacodynamics: 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 (Spiriva Respimat only). The bronchodilation following inhalation of tiotropium is primarily a local effect (on the airways) not a systemic one.
Clinical Trials: Spiriva: The clinical development program included four 1-year and two 6-month randomized, double-blind studies in 2663 patients with COPD (1308 receiving Spiriva). The 1-year program consisted of 2 placebo-controlled and 2 ipratropium-controlled trials. The 6-month trials were both, salmeterol- and placebo-controlled. These studies included evaluation of lung function, dyspnea, exacerbation of COPD and patients assessments of their health-related quality of life.
In the aforementioned studies, Spiriva administered once daily, provided significant improvement in lung function [forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC)] within 30 min following the 1st dose and was maintained for 24 hrs at steady state. Pharmacodynamic steady-state was reached within 1 week with the majority of bronchodilation observed by the 3rd 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 6 long-term trials. These improvements were maintained with no evidence of tolerance.
A randomized, placebo-controlled clinical study in 105 patients with COPD demonstrated that bronchodilation was maintained throughout the 24-hr dosing interval in comparison to placebo regardless of whether Spiriva was administered in the morning or in the evening.
The following health outcome effects were demonstrated in the long-term (6-month and 1-year) trials: Tiotropium significantly improved dyspnea (as evaluated using the Mahler Transitional Dyspnea Index). This improvement was maintained throughout the treatment period.
Spiriva significantly reduced the number of COPD exacerbations and delayed the time to 1st exacerbation in comparison to placebo.
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.
Additionally, in the 1-year placebo-controlled trials, Spiriva significantly reduced the number of hospitalisations associated with COPD exacerbations and delayed the time to 1st hospitalisation.
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: Tiotropium bromide (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. Tiotropium bromide (Spiriva Respimat) significantly improved morning and evening PEFR (peak expiratory flow rate) as measured by patient's daily recordings. The use of Tiotropium bromide (Spiriva Respimat) resulted in a reduction of rescue bronchodilator use compared to placebo.
The bronchodilator effects of Tiotropium bromide (Spiriva Respimat) were maintained throughout the 48-week period of administration with no evidence of tolerance. (See Figures 1 and 2.)

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Day 85, a total of 155, 142 and 152 patients in the Tiotropium bromide (Spiriva), Ipratropium bromide (Atrovent MDI) and placebo groups, respectively completed test day 85. The data for the remaining patients were imputed using last observation or least favourable observation carried forward. (See Figure 3.)

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A combined analysis of two randomised, placebo-controlled, crossover, clinical studies demonstrated that the bronchodilator response for Tiotropium bromide (Spiriva Respimat) (5 μg) was numerically higher compared to Tiotropium bromide (Spiriva) (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) Tiotropium bromide (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 Tiotropium bromide (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 Tiotropium bromide (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 Tiotropium bromide (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)". Tiotropium bromide (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 1. 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 1.)

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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 Tiotropium bromide (Spiriva Respimat) and Spiriva HandiHaler (5,711 patients receiving Tiotropium bromide (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 Tiotropium bromide (Spiriva Respimat) and Spiriva HandiHaler (hazard ratio (Tiotropium bromide (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 Tiotropium bromide (Spiriva Respimat) and 719 days for Spiriva HandiHaler.
The bronchodilator effect of Tiotropium bromide (Spiriva Respimat) was sustained over 120 weeks, and was similar to Spiriva HandiHaler. The mean difference in trough FEV1 for Tiotropium bromide (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 Tiotropium bromide (Spiriva Respimat) and Spiriva HandiHaler (hazard ratio (Tiotropium bromide (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 Tiotropium bromide (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, Tiotropium bromide (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 4).

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At week 24, Tiotropium bromide (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 Tiotropium bromide (Spiriva Respimat) were maintained throughout the 1 year period of administration with no evidence of tachyphylaxis or tolerance (see Figure 5).

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Tiotropium bromide (Spiriva Respimat) significantly reduced the risk of severe asthma exacerbations (see Table 2 and Figure 6).

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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 Tiotropium bromide (Spiriva Respimat) (53.9% versus 46.9%; p=0.0427).
The Asthma Quality of Life Questionnaire (AQLQ(S)) mean scores for Tiotropium bromide (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, Tiotropium bromide (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.
Tiotropium bromide (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 Tiotropium bromide (Spiriva Respimat) had a significantly higher ACQ responder rate at week 24 compared to patients taking placebo (see Table 3).

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In the 12 week GraziaTinA-asthma study in patients who were symptomatic on maintenance treatment with low dose ICS, Tiotropium bromide (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 Tiotropium bromide (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 Tiotropium bromide (Spiriva Respimat)).
Children (1-5 years): one 12-week randomised, double-blind, placebo-controlled study in a total of 101 asthma patients (31 receiving Tiotropium bromide (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, Tiotropium bromide (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, Tiotropium Bromide 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 Tiotropium Bromide (Spiriva Respimat) were maintained throughout the 1 year period of administration with no evidence of tachyphylaxis (see Figure 7).

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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, Tiotropium Bromide (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, Tiotropium bromide (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, Tiotropium Bromide (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 Tiotropium bromide (Spiriva Respimat) were maintained throughout the 1 year period of administration with no evidence of tachyphylaxis (see Figure 8).

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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, Tiotropium bromide (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: Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium bromide is administered by dry powder inhalation or is available as inhalation solution administered by the Respimat inhaler. Generally (for Spiriva) with the inhaled dose or route of administration, the majority of the delivered dose is deposited in the gastrointestinal tract, and to a lesser extent in the intended or target organ, the lung. Approximately 40% of the inhaled dose (of Spiriva Respimat) is deposited in the lungs, the target organ, the remaining amount being deposited in the gastrointestinal tract. Some of the pharmacokinetic data described as follows were obtained with higher doses as recommended for therapy.
Absorption: Following inhalation of dry powder or solution by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable (for Spiriva) and urinary excretion data suggests that approximately 33% of the inhaled dose reaches the systemic circulation (for Spiriva Respimat). It is expected from the chemical structure of the compound (quaternary ammonium compound) that tiotropium bromide is poorly absorbed from the gastrointestinal tract. 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 min (for Spiriva) and 5-7 minutes (for Spiriva Respimat) after inhalation.
Spiriva Respimat: 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: The drug has a plasma protein binding of 72% and shows a volume of distribution of 32 L/kg.
Local concentrations in the lungs are not known, but the mode of administration suggests substantially higher concentrations in the lungs. Studies in rats have shown that tiotropium bromide does not penetrate the blood-brain barrier to any relevant extent.
Spiriva: At steady state, tiotropium bromide plasma levels in COPD patients at peak were 17-19 pg/mL when measured 5 min after dry powder inhalation of a 18-mcg dose, and decreased rapidly in a multi-compartmental manner. Steady-state trough plasma concentrations were 3-4 pg/mL for Spiriva.
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 bromide, 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 bromide even in supra-therapeutic concentrations does not inhibit cytochrome P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.
Elimination: Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers with an interindividual variability of 22%. Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After inhalation of dry powder or the inhalation solution by COPD patients urinary excretion is 14% and 18.6% (0.93 μg), respectively, of the dose, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces.
The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine. After chronic once daily inhalation, pharmacokinetic steady state was reached after 2-3 weeks (for Spiriva) and by day 7 (for Spiriva Respimat) with no accumulation thereafter.
Spiriva: The terminal elimination t½ of tiotropium is between 5 and 6 days following inhalation.
Spiriva Respimat: 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.
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.
Linearity/nonlinearity: Tiotropium demonstrates linear pharmacokinetics in the therapeutic range independent of the formulation.
Specific Populations: Elderly Patients: Spiriva: As expected for all predominantly renally excreted drugs, advanced age was associated with a decrease of tiotropium renal clearance (326 mL/min in COPD patients <58 years to 163 mL/min in COPD patients >70 years) which may be explained by decreased renal function. Tiotropium bromide excretion in urine after inhalation decreased from 14% (young healthy volunteers) to about 7% (COPD patients), however, plasma concentrations did not change significantly with advancing age within COPD patients if compared to inter- and intraindividual variability (43% increase in AUC0-4 hrs after dry powder inhalation).
Spiriva Respimat: 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 AUC0-6,ss or Cmax,ss values.
Exposure to tiotropium was not found to differ with age in patients with asthma.
Paediatric Patients: Spiriva Respimat: 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. Tiotropium bromide (Spiriva Respimat) was administered with a valved holding chamber with facemask in patients 1 to 5 years of age.
Renally Impaired Patients: Spiriva: In common with all other drugs that undergo predominantly renal excretion, renal impairment was associated with increased plasma drug concentrations and reduced renal drug clearance after both IV infusion and dry powder inhalations. Mild renal impairment (CrCl 50-80 mL/min) which is often seen in elderly patients increased tiotropium or tiotropium bromide plasma concentrations slightly (39% increase in AUC0-4 hrs after IV infusion).
In COPD patients with moderate to severe renal impairment (CrCl <50 mL/min), the IV administration of tiotropium or tiotropium bromide resulted in doubling of the plasma concentrations (82% increase in AUC0-4 hrs), which was confirmed by plasma concentrations after dry powder inhalation.
Spiriva Respimat: Following once daily inhaled administration of tiotropium to steady-state in COPD patients with mild renal impairment (CLCR 50-80 mL/min) resulted in slightly higher AUC0-6,ss(between 1.8 to 30% higher) and similar Cmax,ss compared to patients with normal renal function (CLcr >80 mL/min). In COPD patients with moderate to severe renal impairment (CLCR <50 mL/min) the intravenous administration of tiotropium bromide resulted in doubling of the total exposure (82% higher AUC0-4h and 52% higher Cmax) 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 (CLCR 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 repeat-dose studies in rats, mice and dogs were related to anticholinergic properties of tiotropium bromide 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 evidenced 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 series of in vivo and in vitro mutagenicity assays, tiotropium bromide 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.
Indications/Uses
Spiriva: Maintenance treatment of patients with COPD (including chronic bronchitis and emphysema). Maintenance treatment of associated dyspnea, improvement of COPD compromised quality of life and reduction of exacerbations.
Spiriva Respimat: COPD: Tiotropium bromide (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: Tiotropium bromide (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 asthma who remain symptomatic on at least inhaled corticosteroids.
Dosage/Direction for Use
Recommended Dose: Spiriva: Inhalation of the contents of 1 capsule once daily with the HandiHaler inhalation device at the same time of day (see Instructions for Use under Cautions for Usage).
Tiotropium capsules must not be swallowed.
Spiriva Respimat: The recommended dosage of Tiotropium bromide (Spiriva Respimat) is inhalation of the spray of two puffs once daily from the Respimat reusable 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 Tiotropium bromide (Spiriva Respimat).
Special populations: Elderly patients can use Tiotropium bromide (Spiriva Respimat) at the recommended dose. Renally impaired patients can use Tiotropium bromide (Spiriva Respimat) at the recommended dose. However, as with all predominantly renally excreted drugs, Tiotropium bromide (Spiriva Respimat) use should be monitored closely in patients with moderate to severe renal impairment. Hepatically impaired patients can use Tiotropium bromide (Spiriva Respimat) at the recommended dose.
Paediatric population: COPD does not normally occur in children.
In asthma, the recommended dosage of Tiotropium bromide (Spiriva Respimat) in patients 6 to 17 years of age is inhalation of the spray of two puffs once daily from the Respimat reusable inhaler, at the same time of day (see Instructions for use under Cautions for Usage).
The efficacy and safety of Tiotropium bromide (Spiriva Respimat) in paediatric patients below 1 year of age with asthma has not been established.
Overdosage
High doses of Tiotropium bromide (Spiriva/Spiriva Respimat) may lead to anticholinergic signs and symptoms.
Spiriva: However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium in healthy volunteers. Bilateral conjunctivitis in addition to dry mouth was seen in healthy volunteers following repeated once-daily inhalation of 141 mcg in healthy volunteers, which resolved while still under treatment. In a multiple-dose study in COPD patients with a maximum daily dose of 36 mcg tiotropium over 4 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.
Contraindications
Tiotropium bromide (Spiriva/Spiriva Respimat) is contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, e.g. ipratropium or oxitropium or to any component of these products.
Special Precautions
Tiotropium bromide (Spiriva/Spiriva Respimat), as a once daily maintenance bronchodilator, should not be used for the initial treatment of acute episodes of bronchospasm ie, rescue therapy or for the relief of acute symptoms. In the event of an acute attack, a rapid-acting beta-2-agonist should be used.
Immediate hypersensitivity reactions may occur after administration of Tiotropium bromide (Spiriva) inhalation powder or Tiotropium bromide (Spiriva Respimat) inhalation solution.
As with other anticholinergic drugs, Tiotropium bromide (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, Tiotropium bromide (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 Tiotropium bromide (Spiriva) capsules or Tiotropium bromide (Spiriva Respimat). Care must be taken not to allow the powder or 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.
Tiotropium bromide (Spiriva/Spiriva Respimat) should not be used more frequently than once daily.
Tiotropium bromide (Spiriva) capsules are to be used only with the HandiHaler device.
Tiotropium bromide (Spiriva Respimat) cartridges are to be used only with the Respimat reusable inhaler.
Spiriva Respimat: Tiotropium bromide (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 Tiotropium bromide (Spiriva Respimat), even when their symptoms improve.
This medicine contains 0.0011 mg benzalkonium chloride in each actuation.
Benzalkonium chloride may cause wheezing and breathing difficulties. Patients with asthma are at increased risk for these adverse events.
Driving and Using Machines: No studies on the effects on the ability to drive and use machines have been performed. The occurrence of dizziness or blurred vision may influence the ability to drive and use machinery.
Spiriva: Use in pregnancy & lactation: No clinical data on exposed pregnancies are available. Preclinical studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.
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 should not be used in pregnant or nursing women unless the expected benefit outweighs any possible risk to the unborn child or infant.
Use in children: There is no experience with tiotropium in infants and children and therefore should not be used in this age group.
Use In Pregnancy & Lactation
Spiriva: No clinical data on exposed pregnancies are available. Preclinical studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.
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 should not be used in pregnant or nursing women unless the expected benefit outweighs any possible risk to the unborn child or infant.
Spiriva Respimat: Pregnancy: There is a limited amount of data from the use of tiotropium in pregnant women. Pre-clinical studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses (please refer to Pharmacology: Toxicology under Actions). As a precautionary measure, it is preferable to avoid the use of Tiotropium bromide (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, Tiotropium bromide (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 pre-clinical study performed with tiotropium showed no indication of any adverse effect on fertility (please refer to Pharmacology: Toxicology under Actions).
Side Effects
Spiriva: The undesirable effects listed as follows were attributed to the administration of Spiriva based on reasonable grounds to suggest a causal relationship. The frequencies given as follows are reporting incidences regardless of the assessment of causality in any individual case. The information is based on 4 clinical trials involving 906 patients who have been treated with Spiriva over a period of up to 1 year.
Gastrointestinal Tract: 14%: Dry mouth, usually mild, which often resolved with continued treatment; >1% and <10%: Constipation.
Respiratory System: >1% and <10%: Cough and local irritation including throat irritation (as with other inhaled treatment).
Cardiovascular System: >0.1% and <1%: Tachycardia.
In addition, isolated cases of supraventricular tachycardia and atrial fibrillation were reported in association with the use of tiotropium, usually in susceptible patients.
Urinary System: >0.1% and <1%: Difficulty urinating and urinary retention (in men with predisposing factors).
Allergic Reactions: >0.1% and <1%: Hypersensitivity reactions including isolated cases of angioedema.
Most of the previously mentioned adverse reactions can be attributed to the anticholinergic properties of tiotropium. Other anticholinergic effects eg, blurred vision and acute glaucoma may occur. As with other inhaled therapy, inhalation-induced bronchospasm may occur.
Spiriva Respimat: Many of the listed undesirable effects can be assigned to the anticholinergic properties of Tiotropium bromide (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 Tiotropium bromide (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, urticaria, 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.
Paediatric population: The frequency, type, and severity of adverse reactions in the paediatric population are similar as in adults.
Drug Interactions
Although no formal drug interaction studies have been performed, tiotropium inhalation powder or tiotropium bromide has been used concomitantly with other drugs commonly used in the treatment of COPD and asthma (Spiriva Respimat only), including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, antihistamines, mucolytics, leucotriene modifiers, cromones and anti-IgE treatment without adverse drug reactions or clinical evidence of drug interactions.
Spiriva: The co-administration of Spiriva with other anticholinergic-containing drugs has not been studied and is therefore not recommended.
Spiriva Respimat: Common concomitant medications (LABA, ICS and their combinations) used by patients with COPD were not found to alter the exposure to tiotropium.
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 Tiotropium bromide (Spiriva Respimat) is not recommended.
Caution For Usage
Instructions for Use: Spiriva: The HandiHaler device is especially designed for Spiriva. It must not be used to take any other medication. HandiHaler device can be used for up to 1 year to take the medication.
1. Open the dust cap by pulling it upwards, then open the mouthpiece.
2. Remove the Spiriva capsule from the blister (only immediate before use) and place it in the centre chamber. It does not matter which way the capsule is placed in the chamber.
3. Close the mouthpiece firmly until a click is heard, leaving the dust cap open.
4. Hold the HandiHaler device with the mouthpiece upwards and press the piercing button completely at once, and release. This makes holes in the capsule and allows the medication to be released when the patient breathes-in.
5. Breathe-out completely.
Note: Avoid breathing into the mouthpiece at any time.
6. Raise the HandiHaler device to the mouth and close lips tightly around the mouthpiece. Keep head in an upright position and breathe-in slowly and deeply but at a rate sufficient to hear the capsule vibrate. Breathe until lungs are full; then hold breath as long as comfortable and at the same time take the HandiHaler device out of the mouth. Resume normal breathing. Repeat step 5 and 6 once, this will empty the capsule completely.
Open the mouthpiece again. Tip out the used capsule and dispose. Close the mouthpiece and dust cap for storage of the HandiHaler device.
Clean the HandiHaler device 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 device thoroughly by tipping excess water out on a paper towel and air-dry afterwards, leaving the dust cap, mouthpiece and base open.
It takes 24 hrs to air dry, so clean it right after using it and it will be ready for the next dose. Outside of the mouthpiece may be cleaned with a moist but not wet tissue if needed.
The capsules should not be exposed, neither packed nor in the inhaler, to extreme temperatures ie, they should not be exposed to sunlight or to heating.
Spiriva Respimat: Introduction: Children should use Tiotropium bromide (Spiriva Respimat) with an adult's assistance.
Use this inhaler only ONCE A DAY. Each time using it 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 Tiotropium bromide (Spiriva Respimat) reusable inhaler: 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 Tiotropium bromide (Spiriva Respimat) reusable inhaler performance.
If necessary, wipe the outside of the reusable inhaler with a damp cloth.
When to replace the inhaler: When the patient has used an inhaler with 6 cartridges, get a new Tiotropium bromide (Spiriva Respimat) pack containing an inhaler.
Prepare for first use: 1. Remove clear base: Keep the cap closed.
Press the safety catch while pulling off the clear base with the other hand.
2. Insert cartridge: Insert the cartridge into the inhaler.
Place the inhaler on a firm surface and push down firmly until it clicks into place.
3. Track cartridge: Mark the check-box on inhaler's label to track the number of cartridges.
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.
The inhaler is now ready to use and will deliver 60 puffs (30 doses).
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 full open.
Press: Breathe out slowly and fully.
Close the lips around the mouthpiece without covering the air vents. Point the inhaler to the back of the throat.
While taking a slow, deep breath through the mouth, PRESS the dose-release button and continue to breathe in slowly for as long as comfortable.
Repeat Turn, Open, Press for a total of 2 puffs.
Close the cap until the inhaler is used again.
When to replace the Tiotropium bromide (Spiriva Respimat) cartridge: The dose indicator shows how many puffs remain in the cartridge.
Less than 10 puffs remaining. Obtain a new cartridge.
When the cartridge is used up. Turn the clear base to loosen it. The inhaler is now in a locked position. Pull off the cartridge from the inhaler. Insert a new cartridge (continue with step 2).
Storage
Store at temperatures not exceeding 25°C.
Do not freeze.
Spiriva Respimat: Recommended use: 6 cartridges per inhaler.
Use within three months after the cartridge is inserted into the reusable inhaler.
ATC Classification
R03BB04 - tiotropium bromide ; Belongs to the class of other inhalants used in the treatment of obstructive airway diseases, anticholinergics.
Presentation/Packing
Spiriva: Cap (for inhalation) 18 mcg x 30's, Handihaler 1's.
Spiriva Respimat: Inhaler (reusable inhaler + 4 mL cartridge) 2.5 mcg/puff x 60 puffs.
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