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SPIRIVA
RESPIMAT
2.5 microgram, inhalation solution
United Kingdom tiotropium
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Spiriva Respimat 2.5 microgram, inhalation solution
2. QUALITATIVE AND QUANTITATIVE COMPOSITION The delivered dose is 2.5 microgram tiotropium per puff (2 puffs comprise one medicinal dose) and is equivalent to 3.124 microgram tiotropium bromide monohydrate. The delivered dose is the dose which is available for the patient after passing the mouthpiece. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Inhalation solution Clear, colourless, inhalation solution 4. CLINICAL PARTICULARS 4.1 Therapeutic indications COPD Tiotropium is indicated as a maintenance bronchodilator treatment to relieve symptoms of patients with chronic obstructive pulmonary disease (COPD). Asthma Spiriva Respimat is indicated as an add-on maintenance bronchodilator treatment in adult patients with asthma who are currently treated with the maintenance combination of inhaled corticosteroids (≥800 μg budesonide/day or equivalent) and long-acting β 2 agonists and who experienced one or more severe exacerbations in the previous year. 4.2 Posology and method of administration Posology The 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.
In the treatment of asthma the full benefit will be apparent after several doses of the medicinal product. 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 4.4 and 5.2). Hepatically impaired patients can use tiotropium bromide at the recommended dose (see 5.2). Paediatric population COPD There is no relevant use of Spiriva Respimat in children and adolescents below 18 years Cystic fibrosis The efficacy and safety of Spiriva Respimat has not been established (see sections 4.4 and 5.1). Asthma The efficacy and safety of Spiriva Respimat in children and adolescents has not yet been established. Method of administration To ensure proper administration of the medicinal product, the patient should be shown how to use the inhaler by a physician or other health professionals. Instructions For Use Introduction Spiriva Respimat (tiotropium bromide). Read these Instructions for Use before you start using Spiriva Respimat. You will need to use this inhaler only ONCE A DAY. Each time you use it take TWO PUFFS.
- 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 touch the piercing element inside the clear base.
3. Replace clear base
- Put the clear base back into place until it clicks.
- Do not remove the clear base again. 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. Your inhaler is now ready to use. These steps will not affect the number of doses available. After preparation your inhaler will be able to 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 fully open. PRESS
- Breathe out slowly and fully.
- Close your lips around the mouthpiece without covering the air vents. Point your Inhaler to the back of your throat.
- While taking a slow, deep breath through your mouth, PRESS the dose-release button and continue to breathe in slowly for as long as comfortable.
- Hold your breath for 10 seconds or for as long as comfortable.
- Repeat Turn, Open, Press for a total of 2 puffs.
- Close the cap until you use your inhaler again. 4.3 Contraindications Spiriva Respimat is contraindicated in patients with hypersensitivity to tiotropium bromide, atropine or its derivatives, e.g. ipratropium or oxitropium or to any of the excipients (see 6.1). 4.4 Special warnings and precautions for use Tiotropium bromide, as a once daily maintenance bronchodilator, should not be used for the initial treatment of acute episodes of bronchospasm, or for the relief of acute symptoms. In the event of an acute attack a rapid-acting beta- 2 - agonist should be used.
doses (see 5.3). As a precautionary measure, it is preferable to avoid the use of Spiriva Respimat 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 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. 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 5.3). 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. The occurrence of dizziness or blurred vision may influence the ability to drive and use machinery. 4.8 Undesirable effects Summary of the safety profile Many of the listed undesirable effects can be assigned to the anticholinergic properties of tiotropium bromide. Tabulated summary of adverse reactions The 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 pooled from 7 placebo-controlled clinical trials in COPD (3,282 patients) and 6 placebo-controlled clinical trials in asthma (1,256 patients) with treatment periods ranging from four 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, 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 COPD Frequency Asthma Metabolism and nutrition disorders Dehydration Not known Not known Nervous system disorders Dizziness Uncommon Uncommon Headache Uncommon Uncommon Insomnia Rare Uncommon Eye disorders Glaucoma Rare Not known Intraocular pressure increased Rare Not known Vision blurred Rare Not known Cardiac disorders Atrial fibrillation Rare Not known Palpitations Rare Uncommon
System Organ Class / MedDRA Preferred Term Frequency COPD Frequency Asthma Supraventricular tachycardia Rare Not known Tachycardia Rare Not known Respiratory, thoracic and mediastinal disorders Cough Uncommon Uncommon Pharyngitis Uncommon Uncommon Dysphonia Uncommon Uncommon Epistaxis Rare Not known Bronchospasm Rare Uncommon Laryngitis Rare Not known Sinusitis Not known Not known Gastrointestinal disorders Dry Mouth Common Common Constipation Uncommon Rare Oropharyngeal candidiasis Uncommon Uncommon Dysphagia Rare Not known Gastrooesophageal reflux disease Rare Not known Dental caries Rare Not known Gingivitis Rare Rare Glossitis Rare Not known Stomatitis Not known Rare Intestinal obstruction, including ileus paralytic Not known Not known Nausea Not known Not known Skin and subcutaneous tissue disorders, immune system disorders Rash Uncommon Rare Pruritus Uncommon Rare Angioneurotic oedema Rare Rare Urticaria Rare Rare Skin infection/skin ulcer Rare Not known Dry skin Rare Not known Hypersensitivity (including immediate reactions) Not known Rare Anaphylactic reaction Not known Not known Musculoskeletal and connective tissue disorders Joint swelling Not known Not known Renal and urinary disorders Urinary retention Uncommon Not known Dysuria Uncommon Not known Urinary tract infection Rare Not known Description of selected adverse reactions In controlled clinical studies in COPD, the commonly observed undesirable 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 1.2%. In 7 clinical trials in COPD, dry mouth led to discontinuation in 3 of 3,282 tiotropium treated patients (0.1 %). No discontinuations due to dry mouth were reported in 6 clinical trials in asthma (1, patients).
Placebo-controlled studies Lung function Tiotropium inhalation solution, 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 (FEV 1 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 (FEV 1 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. 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. Dyspnoea, Health-related Quality of Life, COPD Exacerbations in long term 1 year studies Dyspnoea 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. Health-related Quality of Life 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. 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 Days to first COPD exacerbation 160 a^86 a^29 (16 to 40)b <0.0001b Mean exacerbation incidence rate 0.78c^ 1.00c^22 0.002c
Study (NSpiriva, Nplacebo) Endpoint Spiriva Respimat Placebo % Risk Reduction (95% CI)a p-value (670, 653) per patient year (8 to 33)c 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 169 a^119 a^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 a (^) Time to first event: days on treatment by when 25% of patients had at least one exacerbation of COPD / hospitalized COPD exacerbation. In study A 25% of placebo patients had an exacerbation by day 112, whereas for Spiriva Respimat 25% had an exacerbation by day 173 ( p=0.09);in study B 25% of placebo patients had an exacerbation by day 74, whereas for Spiriva Respimat 25% had an exacerbation by day 149 (p<0.0001). b (^) Hazard ratios were estimated from a Cox proportional hazard model. The percentage risk reduction is 100(1 - hazard ratio). c (^) Poisson regression. Risk reduction is 100(1 - rate ratio). d (^) Pooling was specified when the studies were designed. The exacerbation endpoints were significantly improved in individual analyses of the two one year studies. 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; 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 FEV 1 (pre-dose). The time to first COPD exacerbation was numericallysimilar during the study with Spiriva Repimat 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). In the post-marketing TIOSPIR study comparing Spiriva Respimat and Spiriva HandiHaler, all-cause mortality (including vital status follow up) was similar with hazard ratio (Spiriva Respimat/Spiriva HandiHaler) = 0.96 , 95% CI 0.84 - 1.09). Respective treatment exposure was 13,135 and 13, patient-years. In the placebo-controlled studies with vital status follow-up to the end of the intended treatment period, Spiriva Respimat showed a numerical increase in all-cause mortality compared to placebo (rate ratio (95% confidence interval) of 1.33 (0.93, 1.92) with treatment exposure to Spiriva Respimat of 2, patient years; the excess in mortality was observed in patients with known rhythm disorders. Spiriva HandiHaler showed a 13 % reduction in the risk of death ((hazard ratio including vital status follow-up (tiotropium/placebo) = 0.87; 95% CI, 0.76 to 0.99)). Treatment exposure to Spiriva HandiHaler was 10,927 patient-years. No excess mortality risk was observed in the subgroup of patients with known
d (^) The rate ratio was obtained from a Poisson regression with log exposure (in years) as offset. The percentage risk reduction is 100 (1-rate ratio). Paediatric population COPD The 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). Asthma The European Medicines Agency has deferred the obligation to submit the results of studies with Spiriva Respimat in one or more subsets of the paediatric population in the treatment of asthma (see section 4. 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 FEV 1 AUC (^0) - 4h and trough FEV 1 ) 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 3. 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 3 : 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) FEV 1 AUC 0 - 4h (% predicted) a absolute changes 3. (1.67, 5.12) <0. 1. (-0.27, 3.55)
- 0. (-4.58, 3.32) 2. (0.50, 4.65) FEV 1 AUC 0 - 4h (litres) absolute changes 0. (0.05, 0.14) <0. 0. (0.02, 0.12)
0. (-0.07, 0.08) 0. (0.03, 0.17) Trough FEV 1 (% predicted) a absolute changes 2. (0.38, 4.06)
1.
- 1. (-5.20, - 271) 2. (0.49, 4.62) Trough FEV 1 (litres) absolute changes 0. (0.01, 0.11)
0. (0.02, 0.12)
- 0. (-0.08, 0.06) 0. (0.03, 0.17) a (^) Co-primary endpoints All Adverse Drug Reactions (ADRs) observed in the CF studies are known undesirable effects of tiotropium (see 4.8). The most commonly observed adverse events considered related during the 12 week double blind period were cough (4.1%) and dry mouth (2.8%).
The number and percentage of patients reporting adverse events (AEs) of special interest in cystic fibrosis irrespective of relatedness are shown in Table 4. Signs and symptoms considered to be manifestations of cystic fibrosis increased numerically, although not statistically significantly, with tiotropium, especially in patients ≤11 years old. Table 4 : Percentage of patients with AEs of special interest in cystic fibrosis by age group over 12 weeks of treatment irrespective of relatedness (pooled Phase II and Phase III) ≤11 years ≥12 years Nplacebo = 96 NSpiriva = 158 Nplacebo = 215 NSpiriva = 307 Abdominal pain 7.3 7.0 5.1 6. Constipation 1.0 1.9 2.3 2. Distal intestinal obstruction syndrome 0.0 0.0 1.4 1. Respiratory tract infections 34.4 36.7 28.4 28. Sputum increased 1.0 5.1 5.6 6. Exacerbations 10.4 14.6 18.6 17. "Distal intestinal obstruction syndrome" and "Sputum increased" are MedDRA preferred terms. "Respiratory tract infections" is the MedDRA higher level group term. "Abdominal pain", "Constipation" and "Exacerbations" are collections of MedDRA preferred terms. Thirty-four (10.9 %) patients randomised to placebo and 56 (12.0%) patients randomised to Spiriva Respimat experienced a serious adverse event. The European Medicines Agency has waived the obligation to submit the results of studies with Spiriva Respimat in the subset of paediatric patients below 1 year of age. 5.2 Pharmacokinetic properties a) General Introduction Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium bromide is available as inhalation solution administered by the Respimat inhaler. Approximately 40% of the inhaled dose is deposited in the lungs, the target organ, the remaining amount being deposited in the gastrointestinal tract. Some of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy. b) General Characteristics of the Active Substance after Administration of the Medicinal Product Absorption: Following inhalation by young healthy volunteers, urinary excretion data suggests that approximately 33% of the inhaled dose reaches the systemic circulation. Oral solutions of tiotropium bromide have an absolute bioavailability of 2-3%. Food is not expected to influence the absorption of this quaternary ammonium compound. Maximum tiotropium plasma concentrations were observed 5-7 minutes after inhalation. At steady state, peak tiotropium plasma levels in COPD patients of 10.5 pg/ml were achieved and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 1.6 0 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. Systemic exposure to tiotropium following the inhalation of tiotropium via the Respimat inhaler was similar to tiotropium inhaled via the HandiHaler device. 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.
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. 5.3 Preclinical safety data Many effects observed in conventional studies of safety pharmacology, repeat-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. 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. 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 was 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. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Benzalkonium chloride Disodium edetate Water, purified Hydrochloric acid 3.6 % (for pH adjustment) 6.2 Incompatibilities Not applicable.
6.3 Shelf life 3 years In-use shelf life: 3 months 6.4 Special precautions for storage Do not freeze. 6.5 Nature and contents of container Type and material of the container in contact with the medicinal product: Solution filled into a polyethylene/polypropylene cartridge with a polypropylene cap with integrated silicone sealing ring. The cartridge is enclosed within an aluminium cylinder. Pack sizes and devices supplied: Single pack: 1 Respimat inhaler and 1 cartridge, providing 60 puffs (30 medicinal doses) Double pack: 2 single packages, each containing 1 Respimat inhaler and 1 cartridge, providing 60 puffs (30 medicinal doses) Triple pack: 3 single packages, each containing 1 Respimat inhaler and 1 cartridge, providing 60 puffs (30 medicinal doses) Eight pack: 8 single packages, each containing 1 Respimat inhaler and 1 cartridge, providing 60 puffs (30 medicinal doses) Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER Boehringer Ingelheim International GmbH Binger Strasse 173 D-55216 Ingelheim am Rhein Germany 8. MARKETING AUTHORISATION NUMBER(S) PL 14598/ 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 24/07/ 10. DATE OF REVISION OF THE TEXT March 2016
