- 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 recommended dosage of tiotropium bromide is inhalation of the contents of one capsule once daily with the HandiHaler device at the same time of day. The recommended dose should not be exceeded.Tiotropium bromide capsules are only for inhalation and not for oral intake.Tiotropium bromide capsules must not be swallowed. Tiotropium bromide should only be inhaled with the HandiHaler device.
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 section 4.4 and section 5.2.Hepatically impaired patients can use tiotropium bromide at the recommended dose (see section 5.2).
COPDThere is no relevant use in the paediatric population (below 18 years) in the indication stated under section 4.1.
Cystic fibrosisThe safety and efficacy of Spiriva 18 microgram in children and adolescents has not been established. No data are available.
Method of administrationTo 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.
Instructions for handling and use
|Remember to carefully follow your doctor's instructions for using SPIRIVA. The HandiHaler is especially designed for SPIRIVA. You must not use it to take any other medication. You can use your HandiHaler for up to one year to take your medication.|
|The HandiHaler 1 Dust cap 2 Mouthpiece 3 Base 4 Piercing button 5 Centre chamber|
|1. To release the dust cap press the piercing button completely in and let go.|
|2. Open the dust cap completely by pulling it upwards. Then open the mouthpiece by pulling it upwards.|
|3. Remove a SPIRIVA capsule from the blister (only immediately before use) and place it in the centre chamber (5), as illustrated. It does not matter which way the capsule is placed in the chamber.|
|4. Close the mouthpiece firmly until you hear a click, 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 you breathe in.|
|6. Breathe out completely. Important: Please avoid breathing into the mouthpiece at any time.|
|7. Raise the HandiHaler to your mouth and close your lips tightly around the mouthpiece. Keep your 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 your lungs are full; then hold your breath as long as comfortable and at the same time take the HandiHaler out of your 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 your HandiHaler device.|
|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 you used it and it will be ready for your next dose. If needed, the outside of the mouthpiece may be cleaned with a moist but not wet tissue.|
|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.|
PregnancyFor tiotropium bromide, no documented clinical data on exposed pregnancies are available. Studies in animals have shown reproductive toxicity associated with maternal toxicity (see section 5.3). The potential risk for humans is unknown. SPIRIVA 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 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.
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 section 5.3).
Summary of the safety profileMany of the listed undesirable effects can be assigned to the anticholinergic properties of SPIRIVA.
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 (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)
|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||Uncommon|
|Intestinal obstruction, including ileus paralytic||Rare|
|Dental caries||Not known|
|Skin and subcutaneous tissue disorders, immune system disorders|
|Hypersensitivity (including immediate reactions)||Rare|
|Anaphylactic reaction||Not known|
|Skin infection, skin ulcer||Not known|
|Dry skin||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 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 populationAn increase in anticholinergic effects may occur with increasing age.
Mechanism of actionTiotropium 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 effectsThe 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 electrophysiologyElectrophysiology: 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 efficacyThe clinical development programme included four one-year and two six-month randomised, double-blind studies in 2663 patients (1308 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 dyspnea, exacerbations and health-related quality of life.In the aforementioned studies, 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.The following health outcome effect was demonstrated in the long term (6-month and one-year) trials:Tiotropium bromide significantly improved dyspnea (as evaluated using the Transition Dyspnea Index.). This improvement was maintained throughout the treatment period.The impact of improvements in dyspnea 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: 640 seconds with SPIRIVA vs. 535 seconds with placebo, compared with a pre-treatment baseline of 492 seconds) and 28.3% (Trial B: 741 seconds with SPIRIVA vs. 577 seconds with placebo, compared with a pre-treatment baseline of 537 seconds).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).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.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).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.Table 1: Summary of exacerbation endpoints
|Endpoint||SPIRIVA 18 microgram (HandiHaler) N = 3,707||Salmeterol 50 microgram (HFA pMDI) N = 3,669||Ratio (95% CI)||p-value|
|Time [days] to first exacerbation||187||145||0.83 (0.77 - 0.90)||<0.001|
|Time to first severe (hospitalised) exacerbation§||-||-||0.72 (0.61 - 0.85)||<0.001|
|Patients with ≥1 exacerbation, n (%)*||1,277 (34.4)||1,414 (38.5)||0.90 (0.85 - 0.95)||<0.001|
|Patients with ≥1 severe (hospitalised) exacerbation, n (%)*||262 (7.1)||336 (9.2)||0.77 (0.66 - 0.89)||<0.001|
Paediatric populationThe European Medicines Agency has waived the obligation to submit results of studies with Spiriva in all subsets of the paediatric population in COPD and cystic fibrosis (see section 4.2 for information on paediatric use).
a) General IntroductionTiotropium 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 below were obtained with higher doses than recommended for therapy.
b) General Characteristics of the Active Substance after Administration of the Medicinal ProductAbsorption: Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable. 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%. Maximum tiotropium bromide plasma concentrations were observed five minutes after inhalation. 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. At steady state, tiotropium bromide plasma levels in COPD patients at peak were 17 19 pg/ml when measured 5 minutes after dry powder inhalation of a 18 microgram dose and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 3-4 pg/ml. 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 dry powder inhalation urinary excretion is 14% 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. After chronic once daily inhalation by COPD patients, pharmacokinetic steady state was reached after 2-3 weeks with no accumulation thereafter.Linearity / Nonlinearity: Tiotropium bromide demonstrates linear pharmacokinetics in the therapeutic range after both intravenous administration and dry powder inhalation.
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 > 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 AUC0-4h 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 inhalations. 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.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: See section 4.2
d) Pharmacokinetic / Pharmacodynamic Relationship(s)There is no direct relationship between pharmacokinetics and pharmacodynamics.
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