- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyThe medicinal product is intended for inhalation use only. The cartridge can only be inserted and used in the Respimat inhaler (see 4.2).Two puffs from the Respimat inhaler comprise one medicinal dose.The recommended dose for adults is 5 microgram tiotropium given as two puffs from the Respimat inhaler once daily, at the same time of the day.The recommended dose should not be exceeded.
Special populationsGeriatric 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 4.4 and 5.2).Hepatically impaired patients can use tiotropium bromide at the recommended dose (see 5.2).Paediatric population
COPDThere is no relevant use of Spiriva Respimat in children and adolescents below 18 years
Cystic fibrosisThe efficacy and safety of Spiriva Respimat has not been established (see sections 4.4 and 5.1).
Method of administrationTo ensure proper administration of the medicinal product, the patient should be shown how to use the inhaler by a physician or other health professionals.
Patient's instructions for use and handling
Spiriva Respimat inhaler and Spiriva Respimat cartridge
1) Inserting the cartridgeThe following steps 1-6 are necessary before first use:
|1||1 With the green cap (A) closed, press the safety catch (E) while pulling off the clear base (G).|
|2a||2 Take the cartridge (H) out of the box. Push the narrow end of the cartridge into the inhaler until it clicks into place. The cartridge should be pushed firmly against a firm surface to ensure that it has gone all the way in (2b). The cartridge will not be flush with the inhaler, you will still see the silver ring of the lower end of the cartridge.|
|2b||Do not remove the cartridge once it has been inserted into the inhaler.|
|3||3 Replace the clear base (G). Do not remove the clear base again.|
2) To prepare the Spiriva Respimat inhaler for first-time use
|4||4 Hold the Spiriva Respimat inhaler upright, with the green cap (A) closed. Turn the base (G) in the direction of the red arrows on the label until it clicks (half a turn).|
|5||5 Open the green cap (A) until it snaps fully open.|
|6||6 Point the Spiriva Respimat inhaler towards the ground. Press the dose release button (D). Close the green cap (A). Repeat steps 4, 5 and 6 until a cloud is visible. Then repeat steps 4, 5 and 6 three more times to ensure the inhaler is prepared for use. Your Spiriva Respimat inhaler is now ready to use.These steps will not affect the number of doses available. After preparation your Spiriva Respimat inhaler will be able to deliver your 60 puffs (30 medicinal doses).|
Daily use of your Spiriva Respimat inhaler
You will need to use this inhaler ONLY ONCE A DAY.
Each time you use it take TWO PUFFS.
|I||I Hold the Spiriva Respimat inhaler upright, with the green cap (A) closed, to avoid accidental release of dose. Turn the base (G) in the direction of the red arrows on the label until it clicks (half a turn).|
|II||II Open the green cap (A) until it snaps fully open. Breathe out slowly and fully, and then close your lips around the end of the mouthpiece without covering the air vents (C). Point your Spiriva Respimat inhaler to the back of your throat. While taking in a slow, deep breath through your mouth, press the dose release button (D) and continue to breathe in slowly for as long as you can. Hold your breath for 10 seconds or for as long as comfortable. III Repeat steps I and II so that you get the full dose.You will need to use this inhaler only ONCE A DAY.Close the green cap until you use your Spiriva Respimat inhaler again.If Spiriva Respimat inhaler has not been used for more than 7 days release one puff towards the ground. If Spiriva Respimat inhaler has 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.|
When to get a new Spiriva Respimat inhaler
|The Spiriva Respimat inhaler contains 60 puffs (30 medicinal doses). The dose indicator shows approximately how much medication is left. When the pointer enters the red area of the scale, there is, approximately, medication for 7 days left (14 puffs). This is when you need to get a new Spiriva Respimat inhaler prescription. Once the dose indicator has reached the end of the red scale (i.e. all 30 doses have been used), the Spiriva Respimat inhaler is empty and locks automatically. At this point, the base cannot be turned any further. At the latest, three months after use the Spiriva Respimat inhaler should be discarded even if not all medication has been used.|
How to care for your inhalerClean 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 your Spiriva Respimat inhaler performance.If necessary, wipe the outside of your Spiriva Respimat inhaler with a damp cloth.
PregnancyFor tiotropium bromide, no clinical data on exposed pregnancies are available. Animal studies have shown reproductive toxicity associated with maternal toxicity (see 5.3). The potential risk for humans is unknown. Spiriva Respimat should therefore only be used during pregnancy when clearly indicated.
Breast-feedingIt 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 Respimat 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 Respimat should be made taking into account the benefit of breast-feeding to the child and the benefit of Spiriva Respimat therapy to the woman.
FertilityClinical 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 5.3).
Summary of the safety profileMany of the listed undesirable effects can be assigned to the anticholinergic properties of tiotropium bromide.
Tabulated summary of adverse reactionsThe frequencies assigned to the undesirable effects listed below are based on crude incidence rates of adverse drug reactions (i.e. events attributed to tiotropium) observed in the tiotropium group (2,802 patients) pooled from 5 placebo-controlled clinical trials with treatment periods ranging from twelve weeks to one year. 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)
|System Organ Class / MedDRA Preferred Term||Frequency|
|Metabolism and nutrition disorders|
|Nervous system disorders|
|Intraocular pressure increased||Rare|
|Respiratory, thoracic and mediastinal disorders|
|Gastrooesophageal reflux disease||Rare|
|Intestinal obstruction, including ileus paralytic||Not known|
|Skin and subcutaneous tissue disorders, immune system disorders|
|Skin infection/skin ulcer||Rare|
|Hypersensitivity (including immediate reactions)||Not known|
|Anaphylactic reaction||Not known|
|Musculoskeletal and connective tissue disorders|
|Joint swelling||Not known|
|Renal and urinary disorders|
|Urinary tract infection||Rare|
Description of selected adverse reactionsIn controlled clinical studies, the commonly observed undesirable effects were anticholinergic undesirable effects such as dry mouth which occurred in approximately 3.2% of patients.In 5 clinical trials, dry mouth led to discontinuation in 3 of 2,802 tiotropium treated patients (0.1 %).Serious undesirable effects consistent with anticholinergic effects include glaucoma, constipation, intestinal obstruction including ileus paralytic and urinary retention.
Other special populationAn increase in anticholinergic effects may occur with increasing age.
Mechanism of actionTiotropium bromide is a long-acting, specific antagonist at muscarinic receptors. It has similar affinity to the subtypes, M1 to M5. In the airways, tiotropium bromide competitively and reversibly binds to the M3 receptors in the bronchial smooth musculature, antagonising the cholinergic (bronchoconstrictive) effects of acetylcholine, resulting in bronchial smooth muscle relaxation. The effect was dose dependent and lasted longer than 24h. 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 effectsThe dissociation of tiotropium from especially M3-receptors is very slow, exhibiting a significantly longer dissociation half-life than ipratropium. 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, very slow receptor dissociation and topical inhaled selectivity found its clinical correlate in significant and long-acting bronchodilation in patients with COPD.
Clinical efficacy and safety in COPDThe clinical Phase III development programme 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.In the aforementioned studies, tiotropium solution for inhalation, 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 (FEV1 mean improvement at 30 minutes: 0.113 litres; 95% confidence interval (CI): 0.102 to 0.125 litres, p< 0.0001). Improvement of lung function was maintained for 24 hours at steady state compared to placebo (FEV1 mean improvement: 0.122 litres; 95% CI: 0.106 to 0.138 litres, p< 0.0001).Pharmacodynamic steady state was reached within one week.Spiriva Respimat significantly improved morning and evening PEFR (peak expiratory flow rate) as measured by patient's daily recordings compared to placebo (PEFR mean improvement: mean improvement in the morning 22 L/min; 95% CI: 18 to 55 L/min, p< 0.0001; evening 26 L/min; 95% CI: 23 to 30 L/min, p<0.0001). The use of Spiriva Respimat resulted in a reduction of rescue bronchodilator use compared to placebo (mean reduction in rescue use 0.66 occasions per day, 95% CI: 0.51 to 0.81 occasions per day, p<0.0001). The bronchodilator effects of Spiriva Respimat were maintained throughout the 1-year period of administration with no evidence of tolerance.The following health outcome effects were demonstrated in the long term 1-year studies:(a) Spiriva Respimat significantly improved dyspnoea (as evaluated using the Transition Dyspnoea Index) compared to placebo (mean improvement 1.05 units; 95% CI: 0.73 to 1.38 units, p<0.0001). An improvement was maintained throughout the treatment period.(b) The improvement in mean total score of patient's evaluation of their Quality of Life (as measured using the St. George's Respiratory Questionnaire) between Spiriva Respimat versus placebo at the end of the two 1-year studies was 3.5 units (95% CI: 2.1 to 4.9, p<0.0001). A 4-unit decrease is considered clinically relevant.(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 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.Table 1: Statistical Analysis of Exacerbations of COPD and Hospitalized COPD Exacerbations in Patients with Moderate to Very Severe COPD
|Study (NSpiriva, Nplacebo)||Endpoint||Spiriva Respimat||Placebo||% Risk Reduction (95% CI)a||p-value|
|1-year Ph III studies, pooled analysisd(670, 653)||Days to first COPD exacerbation||160a||86a||29 (16 to 40)b||<0.0001b|
|Mean exacerbation incidence rate per patient year||0.78c||1.00c||22 (8 to 33)c||0.002c|
|Time to first hospitalised COPD exacerbation||25 (-16 to 51)b||0.20b|
|Mean hospitalised exacerbation incidence rate per patient year||0.09 c||0.11 c||20 (-4 to 38) c||0.096 c|
|1-year Ph IIIb exacerbation study (1939, 1953)||Days to first COPD exacerbation||169a||119a||31 (23 to 37)b||<0.0001b|
|Mean exacerbation incidence rate per patient year||0.69c||0.87c||21 (13 to 28)c||<0.0001c|
|Time to first hospitalised COPD exacerbation||27 (10 to 41)b||0.003b|
|Mean hospitalised exacerbation incidence rate per patient year||0.12c||0.15c||19 (7 to 30)c||0.004c|
COPDThe European Medicines Agency has waived the obligation to submit the results of studies with Spiriva Respimat in all subsets of the paediatric population in COPD (see section 4.2 for information on paediatric use).
Clinical efficacy and safety in cystic fibrosis (CF):The clinical development programme in CF included 3 multicentre studies in 959 patients aged 5 months and above. Patients below 5 years used a spacer (AeroChamber Plus®) with face mask and were included for safety assessment only. The two pivotal studies (a dose finding Phase II study and a confirmatory Phase III study) compared lung function effects (percent predicted FEV1 AUC 0-4h and trough FEV1) of Spiriva Respimat (tiotropium 5 µg: 469 patients) versus placebo (315 patients) in 12-weeks randomised, double-blind periods; the Phase III study also included a long term open label extension, up to 12 months. In these studies, all respiratory medications, except anticholinergics, were allowed as concomitant treatment, e.g. long acting beta agonists, mucolytics and antibiotics.Effects on lung function are displayed in Table 2. No significant improvement in symptoms and health status (exacerbations by Respiratory and Systemic Symptoms Questionnaire and quality of life by Cystic Fibrosis Questionnaire) have been observed. Table 2: Adjusted mean difference from placebo for absolute changes from baseline after 12 weeks
|Phase II||Phase III|
|All patients (NSpiriva = 176, Nplacebo = 168)||All patients (NSpiriva = 293, Nplacebo = 147)||≤11 years||≥12 years|
|(NSpiriva = 95, Nplacebo = 47)||(NSpiriva = 198, Nplacebo = 100)|
|mean(95% CI)||p-value||mean(95% CI)||p-value||mean(95% CI)||mean(95% CI)|
|FEV1AUC0-4h (% predicted) aabsolute changes||3.39(1.67, 5.12)||<0.001||1.64(-0.27, 3.55)||0.092||-0.63(-4.58, 3.32)||2.58(0.50, 4.65)|
|FEV1AUC0-4h (litres) absolute changes||0.09(0.05, 0.14)||<0.001||0.07(0.02, 0.12)||0.010||0.01(-0.07, 0.08)||0.10(0.03, 0.17)|
|Trough FEV1 (% predicted) aabsolute changes||2.22(0.38, 4.06)||0.018||1.40-0.50, 3.30||0.150||-1.24(-5.20, - 271)||2.56(0.49, 4.62)|
|Trough FEV1 (litres) absolute changes||0.06(0.01, 0.11)||0.028||0.07(0.02, 0.12)||0.012||-0.01(-0.08, 0.06)||0.10(0.03, 0.17)|
|≤11 years||≥12 years|
|Nplacebo = 96||NSpiriva = 158||Nplacebo = 215||NSpiriva = 307|
|Distal intestinal obstruction syndrome||0.0||0.0||1.4||1.3|
|Respiratory tract infections||34.4||36.7||28.4||28.3|
a) General IntroductionTiotropium 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. Approximately 40% of the inhaled dose is deposited in the lungs, the target organ, the remaining amount being deposited in the gastrointestinal tract. Some of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy.
b) General Characteristics of the Active Substance after Administration of the Medicinal ProductAbsorption: Following inhalation of the solution by young healthy volunteers, urinary excretion data suggest that approximately 33% of the inhaled dose reach the systemic circulation. It is expected from the chemical structure of the compound (quaternary ammonium compound) and from in-vitro experiments that tiotropium bromide is poorly absorbed from the gastrointestinal tract (10-15%). Oral solutions of tiotropium bromide have an absolute bioavailability of 2-3%. At steady state, tiotropium bromide plasma levels in COPD patients at peak were 10.5-11.7 pg/ml when measured 10 minutes after administration of a 5 microgram dose delivered by the Respimat inhaler and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 1.49-1.68 pg/ml. Food is not expected to influence the absorption of this quaternary ammonium compound.Distribution: The drug is bound by 72% to plasma proteins 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 terminal elimination half-life of tiotropium bromide is between 5 and 6 days following inhalation. 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 the solution urinary excretion is 20.1-29.4 % of the dose, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces. The renal clearance of tiotropium bromide exceeds the creatinine clearance, indicating secretion into the urine. Linearity / Nonlinearity: Tiotropium bromide demonstrates linear pharmacokinetics in the therapeutic range after intravenous administration, dry powder inhalation and inhalation of the solution.
c) Characteristics in PatientsGeriatric Patients: As expected for all predominantly renally excreted drugs, advanced age was associated with a decrease of tiotropium bromide renal clearance (326 ml/min in COPD patients < 58 years to 163 ml/min in COPD patients > 70years) 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 AUC0-4h after dry powder inhalation).Renally Impaired Patients: 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 intravenous infusion and dry powder inhalation. Mild renal impairment (CLCR 50-80 ml/min) which is often seen in elderly patients increased tiotropium bromide plasma concentrations slightly (39% increase in AUC0-4h after intravenous infusion). In COPD patients with moderate to severe renal impairment (CLCR < 50 ml/min) the intravenous administration of tiotropium bromide resulted in doubling of the plasma concentrations (82% increase in AUC0-4h), which was confirmed by plasma concentrations after dry powder inhalation and also by inhalation of the solution via the Respimat inhaler.Hepatically Impaired Patients: Liver insufficiency is not expected to have any relevant influence on tiotropium bromide pharmacokinetics. Tiotropium bromide is predominantly cleared by renal elimination (74% in young healthy volunteers) and simple non-enzymatic ester cleavage to pharmacologically inactive products.Paediatric Patients: There were no paediatric patients in the COPD programme (see 4.2). Paediatric patients were studied as part of the CF clinical programme also covering adults. Following inhalation of 5 µg tiotropium, the tiotropium plasma level in CF patients ≥5 years was 10.1 pg/ml 5 minutes post-dosing at steady-state and decreased rapidly thereafter. The fraction of the dose available in CF patients <5 years old who used the spacer and mask was approximately 3- to 4-fold lower than that observed in CF patients 5 years and older. Tiotropium exposure was related to body-weight in CF patients <5 years.
d) Pharmacokinetic / Pharmacodynamic Relationship(s)There is no direct relationship between pharmacokinetics and pharmacodynamics.
Boehringer Ingelheim Limited
Ellesfield Avenue, Bracknell, Berkshire, RG12 8YS
+44 (0)1344 741 298
+44 (0)1344 424 600
+44 (0)1344 742579