长效噻托溴铵吸入喷雾剂Spiriva Respimat于2014年9月25日获美国FDA批准
1 With the green cap (A) closed, press the safety catch (E) while pulling off the clear base (G). 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).
2) To prepare the Spiriva Respimat inhaler for first-time use
6 Point the Spiriva Respimat inhaler towards the ground.
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. III Repeat steps I and II so that you get the full dose.
In controlled clinical studies in COPD, the commonly observed undesirable effects were anticholinergic undesirable effects such as dry mouth which occurred in approximately 3.2% of patients. In asthma the incidence of dry mouth was 1.2%. In 5 clinical trials in COPD, dry mouth led to discontinuation in 3 of 2,802 tiotropium treated patients (0.1 %). No discontinuations due to dry mouth were reported in 6 clinical trials in asthma (1,256 patients). Serious undesirable effects consistent with anticholinergic effects include glaucoma, constipation, intestinal obstruction including ileus paralytic and urinary retention. Other special population An increase in anticholinergic effects may occur with increasing age. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard 4.9 Overdose High doses of tiotropium bromide may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 340 microgram tiotropium bromide in healthy volunteers. Additionally, no relevant adverse effects, beyond dry mouth/throat and dry nasal mucosa, were observed following 14-day dosing of up to 40 microgram tiotropium solution for inhalation in healthy volunteers with the exception of pronounced reduction in salivary flow from day 7 onwards. Acute intoxication by inadvertent oral ingestion of tiotropium solution for inhalation from the cartridge is unlikely due to low oral bioavailability. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, anticholinergics ATC code: R03B B04 Mechanism of action Tiotropium 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 effects The 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 and asthma. Clinical efficacy and safety in COPD The 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
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. In a retrospective pooled analysis of the three 1-year and one 6-month placebo-controlled trials with Spiriva Respimat including 6,096 COPD patients a numerical increase in all-cause mortality was seen in patients treated with Spiriva Respimat (68; incidence rate (IR) 2.64 cases per 100 patient-years) compared with placebo (51, IR 1.98) showing a rate ratio (95% confidence interval) of 1.33 (0.93, 1.92) for the planned treatment period; the excess in mortality was observed in patients with known rhythm disorders. Clinical efficacy and safety in asthma The clinical Phase III programme for persistent asthma included two 1-year randomised, double-blind, placebo-controlled studies in a total of 907 asthma patients (453 receiving Spiriva Respimat) on a combination of ICS (≥800 µg budesonide/day or equivalent) with a LABA. The studies included lung function measurements and severe exacerbations as primary endpoints. PrimoTinA-asthma studies In the two 1-year studies in patients who were symptomatic on maintenance treatment of at least ICS (≥800 µg budesonide/day or equivalent) plus LABA, Spiriva Respimat showed clinically relevant 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. In the PrimoTinA-asthma studies, treatment of symptomatic patients (N=453) with ICS plus LABA plus tiotropium reduced the risk of severe asthma exacerbations by 21% as compared to treatment of symptomatic patients (N=454) with ICS plus LABA plus placebo. The risk reduction in the mean number of severe asthma exacerbations/patient year was 20%. This was supported by a reduction of 31% in risk for asthma worsening and 24% risk reduction in the mean number of asthma worsenings/patient year (see Table 2). Table 2: Exacerbations in Patients Symptomatic on ICS (≥800 µg budesonide/day or equivalent) plus LABA (PrimoTinA-asthma studies)
b Hazard ratio, confidence interval and p-value obtained from a Cox proportional hazards model with only treatment as effect. The percentage risk reduction is 100(1 - hazard ratio). c Time to first event: days on treatment by when 25%/50% of patients had at least one severe asthma exacerbation/worsening of asthma 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 4.2 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 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
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)
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 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 Product Absorption: 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%. Food is not expected to influence the absorption of this quaternary ammonium compound. 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. 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 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 by healthy volunteers and COPD patients. The effective half-life was 34 hours in patients with asthma. Total clearance was 880 ml/min after an intravenous dose in young healthy volunteers with an interindividual variability of 22%. Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After inhalation of the solution by healthy volunteers 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. In patients with asthma, 11.9% (0.595 µg) of the dose is excreted unchanged in the urine over 24 hours post dose at steady state. The renal clearance of tiotropium 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 Patients Geriatric 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). Exposure to tiotropium was not found to differ with age in patients with asthma. 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. 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 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. 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 and other handling 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 14598/0084 9. Date of first authorisation/renewal of the authorisation 24/07/2012 10. Date of revision of the text 09/2014 ------------------------------------------------------ 产地国家: 美国 原产地英文商品名: Spiriva Respimat 2.5mcg Solution for Inhalation 4ml 原产地英文药品名: Tiotropium 中文参考商品译名: 适喘樂 舒沛喷 吸入剂 2.5 微公克 4毫升 中文参考药品译名: 噻托溴铵 生产厂家英文名: Boehringer Ingelheim ------------------------------------------------------ 产地国家: 德国 原产地英文商品名: Spiriva Respimat 2.5mcg Solution for Inhalation 4ml 原产地英文药品名: Tiotropium 中文参考商品译名: 适喘樂 舒沛喷 吸入剂 2.5 微公克 4毫升 中文参考药品译名: 噻托溴铵 生产厂家英文名: Boehringer Ingelheim |
Spiriva Respimat(Tiotropium)噻托溴铵吸入喷雾剂简介:
长效噻托溴铵吸入喷雾剂Spiriva Respimat于2014年9月25日获美国FDA批准近日,美国FDA批准勃林格殷格翰制药公司的Spiriva Respimat(Tiotropium Bromide Inhalation Spray,噻托溴铵吸入喷雾剂每日一次喷 ... 责任编辑:admin |
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