药品信息:
成分
每喷一次（噗）含噻托溴铵2.5微克，相当于噻托溴铵水合物（=
噻托溴铵）3.124微克
喷二次为一个剂量（INN=噻托溴铵）
药理学性质
药效学性质
药物类别：抗胆碱剂（抗胆碱能药物）
ATC代码：R03B B04
噻托溴铵为长效，专一性的蕈毒碱接受体（毒蕈碱受体）拮抗
剂，对各种接受体亚型（M1至M5）均有相似的亲和力。在呼吸道中，噻托溴铵
可與支氣管平滑肌組織上的M3接受體發生競爭性且可逆的結合，因而對乙醯膽鹼
(acetylcholine)的膽素激性作用(支氣管收縮)具有拮抗效果，而使支氣管平滑肌放
松。此效果与剂量高低有关，且可持续长达24小时以上.Tiotropium溴化物为四级
銨(N-quaternary)之抗膽鹼劑，吸入後可局部選擇性地作用於支氣管，在產生有效治
療濃度時仍還不會產生全身性抗膽鹼作用。Tiotropium與M3接受體的分離速度很慢，
其分離半衰期很顯著地長於ipratropium。在體外功能性試驗中，tiotropium與M2接受
體分離的速度較M3快，因此以動力學的角度而言，對M3接受體的選擇性高於M2。由於
tiotropium與接受體作用強且分離速度慢，而且局部吸入時具有選擇性，因此在臨床
上治疗慢性阻塞性肺病患者时，具有显著且长效的支气管扩张作用。
第三期臨床試驗包括2個為期一年、2個為期12週與2個為期4週的隨機分組、雙盲研究，
共收录2901名慢性阻塞性肺病患者（其中1038人使用5μg的噻托溴铵）。为期一年的研究计画包括
2個以安慰劑為對照組的試驗。2個為期12週的試驗則以活性藥物(ipratropium)與安慰
劑為對照組。6個臨床試驗均納入肺功能評量，此外，2個為期一年的研究中亦評量呼
吸困难，健康相关生活品质与对病情恶化之影响等健康结果指标。
在上述研究中，相较于安慰剂，每天使用一次噻托溴铵吸入剂，在使用第一次剂量
后30分钟内可使肺功能（第一秒吐气量的FEV1与肺活量FVC）明显改善（30分钟时FEV1平
均改善：0113公升，95％信赖区间[CI]为：0102至0125公升，P <0.0001）。
相較於安慰劑，肺功能改善效果在穩定狀態時可持續24小時（FEV1平均改善：0.122公
升95％CI：0106至0138公升，P <0.0001）。
药效可于一周内达到稳定状态BPI号码：0269-002006年3月21日
+2007年欧盟的SPC版第5
2月11日
依据病患每日之纪录，思力RESPIMAT，相较于安慰剂可显著改善早晨与晚上的最
高吐气流速（呼气峰流速，PEFR）（PEFR平均改善：早晨平均改善22
L / min时，95％CI为：18至55升/分，P <0.0001;晚上平均改善26升/分，95％CI：23至
30升/分，P <0.0001）。相较于安慰剂，使用思力RESPIMAT可降低使用急救用支
气管扩张剂的使用次数（急救药物使用平均减少0.66次/天，95％CI：0.51至0.81次/
天，P <0.0001）。
思力RESPIMAT的支气管扩张作用在一年使用期间均能持续维持，且不会产生耐药
性。
在为期一年的长期研究中，可显现以下健康结果指标疗效：
（一）相较于安慰剂，思力RESPIMAT可显著改善呼吸困难症状（以短暂呼吸困难指
数【过渡呼吸困难指数]评估）（平均改善1.05单位，95％CI：0.73至1.38
单位，P <0.0001）。于整个治疗期间均可有效维持改善效果。
（二）在2个为期一年的研究结束时，相较于安慰剂组，思力RESPIMAT组病患对其生
活品质评估（以圣乔治呼吸问卷[街乔治呼吸问卷]评量）
的总分平均改善3.5单位（95％CI：2.1至4.9，P <0.0001）。降低4单位可视为具临床意
义。
（三）思力RESPIMAT可显著减少慢性阻塞性肺病恶化之次数（研究à每年平均减少21％，95％CI：
每年减少1％至37％，P =0.04;研究B：每年平均减少23％，95％CI为：每年减少4％至38％，
P =0.02;研究à与乙合并：每年平均减少22％，95％CI为：每年减少8％至33％，P =0.002），
並延緩首次出現病情惡化的時間（研究A：安慰劑組病患有四分之一於第112天前發生
病情恶化，思力RESPIMAT组病患则为第173天，P =0.09;研究B：安慰剂组病患有
四分之一于第74天前发生病情恶化，思力RESPIMAT组病患则为第149天，
p<0.0001；研究A與B合併：安慰劑組病患有四分之一於第86天前發生病情惡化，Spiriva
RESPIMAT组病患则为第160天，P <0.0001）。
药物动力学性质
一）一般性质介绍
噻托溴铵为一种非旋光活性（非手性）的四级铵化合物，略溶于水，现
有的吸入液係以Respimat吸入器投藥。吸入的藥物約有40%進入於目標器官肺部，其餘
的量則進入於腸胃道。下述藥物動力學數據有些是使用比建議劑量高的劑量。
二）本药品吸入体内之后其活性物质的一般特性
吸收：年輕健康自願者吸入藥液之後，其從尿液排除的數據顯示，吸入的藥物約有33%
到達全身循環。由此化合物的化學構造（四級銨化合物）與體外實驗數據，預期
噻托溴铵在肠胃道不易被吸收（10-15％）。噻托溴铵口服溶液
的絕對生體可用率為2-3%。在穩定狀態下，以Respimat吸入器吸入5微克（microgram）
剂量10分钟后，慢性阻塞性肺病患者血中的噻托溴铵最高浓度为10.5-11.7皮克/毫升，接
着以多室（多功能隔室）方式快速下降，稳定状态下之最低血中浓度为
1.49-1.68皮克/毫升。预期食物不会影响此四级铵化合物的吸收。
分布：此药物与血中蛋白质的结合率为72％，分布体积（分布容积）
为32 l/kg。無法得知肺部的局部濃度，但此種給藥方式顯示在肺部應該有更高的濃BPI编号：0269-002006年3月21日
+2007年欧盟的SPC版第5
3月11日
度。在大鼠的实验显示，噻托溴铵无法穿透血脑屏障。
生物转化（生物转化）：噻托溴铵的生物转化率极低，其证据
来自年轻健康自愿者以静脉注射后，有74％的药物以原型经由尿液排除.Tiotropium
溴化物为一酯类，可不经由酵素而切断为醇类（N-methylscopine）与酸类化合物
（Dithienylglycolic酸），两者皆不会与蕈毒碱接受体结合，在人类肝脏微粒体
（微粒）与人类肝细胞的体外实验中，显示有一些药物（小于20％之静脉注射剂
量）被细胞色素P450（细胞色素P450，CYP）以氧化方式代谢，接着与麸胺基硫
（谷胱甘肽）结合成第二阶段代谢物（II期代谢产物）。
肝脏微粒体的体外研究显示，此酵素代谢途径会被CYP2D6（及3A4）抑制剂（如
奎尼丁，酮康唑与孕二烯酮）所抑制，显示CYP2D6及3A4与其代谢途径
有关，这些酵素负责小部分药物的排除。即使超过治疗剂量的噻托溴铵，
亦不会抑制人类肝脏微粒体之CYP1A1,1A2,2B6,2C9,2C19,2D6,2E1或3A。
清除：噻托溴铵经吸入后，末相排除半衰期在5至6天之间年轻健康自
愿者以静脉注射后之总清除率为880毫升/分，个体之间的差异为22％。静脉注射的
噻托溴铵主要以原型经尿液排除（74％）。以溶液形式吸入时，有20.1-29.4
％的劑量經尿液排除，其餘大部分未被腸道吸收的藥物則經由糞便排除。Tiotropium
溴化物之肾脏清除率超过肌酸酐（肌酐）之清除率，表示它会经由主动分泌
排泄到尿液中。
线性/非线性：噻托溴铵在治疗范围内，无论是静脉注射，干粉吸入或溶
液吸入，其药物动力学均呈线性关系。
Ç特殊族群
老年病患：與其他主要由腎臟排除之藥物相同，可以預期在年紀較大之病患可能因為
肾脏功能降低，而使得噻托溴铵的肾脏清除率降低（小于58岁之慢性阻塞性肺病
病患的清除率为326毫升/分钟，大于70岁之COPD病患的清除率则为163毫升/分钟）。
噻托溴铵吸入后从尿液排除的量，由年轻健康自愿者的14％降至患慢性阻塞性肺病
者的7％，然而，若相较于个体间差异及个体内差异，年纪较长之COPD病患的血中浓
度并没有显著的改变（以干粉吸入方式使用后AUC0-4h增加43％）。
腎功能受損病患：與所有其它主要由腎臟排除之藥物相同，不論是以靜脈注射或乾粉
吸入方式使用，腎臟功能損害均會導致血中藥物濃度升高與腎臟清除率降低。年老患
者常有轻微肾脏受损（CLCR50-80毫升/分钟），会稍微增加噻托溴铵血中浓
度（静脉输注后AUC0-4h增加39％）。在中度或严重肾功能受损（CLCR<50毫升/分钟）之
慢性阻塞性肺病病患，静脉注射噻托溴铵会使血中浓度增加两倍（AUC0-4h增加82％），
以干粉吸入方式或以RESPIMAT吸入器吸入溶液之后的血中浓度亦有同样情形。
肝功能受损病患：肝功能不全对于噻托溴铵之药物动力学应不会有影响。
噻托溴铵主要是经由肾脏排除（在年轻健康自愿者占74％），以及借着简单
的非酵素性酯断裂形成无药物活性的代谢物。
儿童病患：请参阅用法用量
D）药物动力学/药效学之间的关系
药物动力学与药效学之间无直接关系BPI号码：0269-002006年3月21日
+2007年欧盟的SPC版第5
4月11日
临床前安全性数据
在安全性藥理學、多劑毒性與生殖毒性的傳統研究中，所觀察到的許多作用均可歸因
于噻托溴铵的抗胆碱作用性质。在动物实验中通常可观察到食量减少，体
重未增加、口鼻乾燥、淚液與唾液分泌減少、瞳孔放大與心跳加速。多劑毒性研究中
所發現的其他相關作用為：大鼠與小鼠由鼻炎以及鼻腔與喉頭之上皮變化所引起的呼
吸道輕度刺激，以及大鼠的攝護腺炎與伴隨發生於膀胱之蛋白質沉積與結石。
對懷孕、胚胎／胎兒發育、分娩或產後發育的影響上，僅在對母體具毒性的劑量始顯
现有害作用.Tiotropium溴铵对大鼠与兔子均不具致畸性。局部或全身性暴露量
超过治疗暴露量5倍时，可能引发呼吸道（刺激）或泌尿生殖器（摄护腺炎）的变化
与生殖毒性，基因毒性与致癌性之研究均显示噻托溴铵对人体无特殊危险
性。
适应症
慢性阻塞性肺疾（包括慢性支气管炎及肺气肿）之维持治疗。
用法用量
本药须由医师处方使用
SPIRIVA RESPIMAT推荐剂量为每日一次，每次定时按二次喷药（请参见“使用说
明“使用本药）。
年老者可依推荐剂量使用。
腎功能受損病人可依推薦劑量使用。但是與其他主要經由腎臟排泄之藥物相同，當使
用于中度到严重肾功能受损病人时，需严密监控病情。
肝功能受损病人可依推荐剂量使用。
慢性阻塞性肺病通常不会发生于儿童.SPIRIVA RESPIMAT尚无小儿之安全性及有效性资料。
因此不建议使用于此年龄群。
使用说明
请详阅并小心地依照使用说明使用本药
Ingredients
Each spray once (puff) containing 2.5 micrograms tiotropium bromide, tiotropium bromide monohydrate equivalent (=
Tiotropium) 3.124 micrograms
Spray twice for a dose (INN = tiotropium)
Pharmacological properties
Pharmacodynamic properties
Drug classes: anticholinergic agents (anticholinergics)
ATC code: R03B B04
Tiotropium is a long-term, specific muscarinic receptors (muscarinic receptor) antagonist
Agents, for a variety of receptor subtypes (M1 to M5) have similar affinities. In the respiratory tract, tiotropium
Competition can occur and M3 receptors on bronchial smooth muscle tissue and reversible binding, and thus acetylcholine
(acetylcholine) of choline stimulated role (bronchoconstriction) has an antagonistic effect, leaving the bronchial smooth muscle release
Loose. This effect was dose-related level, and sustainable for more than 24 hours .Tiotropium bromide for four
Ammonium (N-quaternary) of anticholinergic agents, inhalation can be partially selective effect on bronchial, in an effective governance
Is yet still not produce a systemic anticholinergic effects at therapeutic concentrations. Tiotropium and M3 body to accept the separation speed is very slow,
Its half-life is significantly longer than the separation ipratropium. In vitro functional assays, tiotropium and M2 accept
M3 body faster than the speed of separation, and therefore the kinetic point of view, the selectivity to the M3 receptor is higher than M2. Since
tiotropium and acceptor separation of the role of strong and slow and selective topical inhaled, so the clinical
When the treatment of patients with chronic obstructive pulmonary disease, with significant and long-acting bronchodilator effect.
Phase III clinical trials, including two one-year, two for a period of 12 weeks with two 4-week randomized, double-blind study,
Contains a total of 2901 patients with chronic obstructive pulmonary disease (of which 1038 people use 5μg of tiotropium). A one-year research project, including
Two placebo-controlled trials group. Two 12-week trial places the active drug (ipratropium) and comfort
Agents for the control group. Six clinical trials were included lung function assessment, in addition, two one-year evaluation study also call
Dyspnea, health-related quality of life health impact and outcome indicators of disease progression and so on.
In the study, compared to placebo, once daily tiotropium inhaler, using the first dose
After lung function can (FEV1 and FVC of FEV1 FVC) improved significantly within 30 minutes (30 minutes flat when FEV1
Were improved: 0113 liters, 95% confidence interval [CI],: 0102-0125 liters, P <0.0001).
Sustainable 24 hours (FEV1 mean improvement compared to placebo in improving lung function results in a steady state: 0.122 public
L 95% CI: 0106 至 0138 liters, P <0.0001).
Pharmacodynamic steady state can be achieved within a week BPI number: 0269-002006 On March 21
+2007 EU's SPC Version 5
February 11
According to the records of patients daily, Spiriva RESPIMAT, compared with placebo significantly improved the most in the morning and evening on
High expiratory flow rate (peak expiratory flow rate, PEFR) (PEFR mean improvement: Morning average improvement 22
When L / min, 95% CI of: 18 to 55 l / min, P <0.0001; mean improvement at 26 l / min, 95% CI: 23 to
30 l / min, P <0.0001). Compared with placebo, the use of Spiriva RESPIMAT can reduce the use of first aid support
The frequency of use of bronchodilators (rescue medication use an average reduction of 0.66 times / day, 95% CI: 0.51 至 0.81 times /
Days, P <0.0001).
Bronchodilator effect of Spiriva RESPIMAT can continue to maintain a one-year period, and will not produce drug
Sex.
In long-term studies for one year, you can show the efficacy of the following health outcome indicators:
(A) compared to placebo, Spiriva RESPIMAT can significantly improve symptoms of dyspnea (difficulty breathing refers to short-term
Number [transitional dyspnea index] assessment) (mean improvement 1.05 units, 95% CI: 0.73 至 1.38
Units, P <0.0001). Throughout the period of treatment can effectively maintain improvement.
(B) at the end of the two year study, compared to the placebo group, Spiriva RESPIMAT group had its birth
Living quality assessment (to St. George's Respiratory Questionnaire [St. George's Respiratory Questionnaire] Assessment)
The average improvement of 3.5 units of the total score (95% CI: 2.1 至 4.9, P <0.0001). Reduce the four units can be regarded as a clinical meaning
Righteousness.
(C) Spiriva RESPIMAT can significantly reduce the frequency of worsening of chronic obstructive pulmonary disease (research à average reduction of 21% per year, 95% CI:
Reduction of 1% per year 至 37%, P = 0.04; study B: average annual reduction of 23%, 95% CI is: reduce 4-38% per year,
P = 0.02; research à merger with B: average annual reduction of 22%, 95% CI is: reduce 8-33% per year, P = 0.002),
Time delay disease progression and first appeared (Study A: placebo patients had a fourth on the first 112 days before they occur
Condition deteriorated, Spiriva RESPIMAT group of patients, compared with the first 173 days, P = 0.09; study B: placebo patients had
Fourth in the first 74 days prior to the occurrence of disease progression, compared with Spiriva RESPIMAT group had the first 149 days,
p <0.0001; study A and B merge: a quarter of the patients in the placebo group in the first 86 days prior to the occurrence of disease progression, Spiriva
RESPIMAT group of patients, compared with the first 160 days, P <0.0001).
Pharmacokinetic properties
A) the general nature of the presentation
Tiotropium is a non-optically active (non-chiral) quaternary ammonium compound, slightly soluble in water, now
Some Respimat inhaler with inhalation dosing liquid system. Approximately 40% of drug inhaled into the lungs to the target organ, the rest
The amount is entered in the gastrointestinal tract. Some of the pharmacokinetic data following high-dose than the recommended dose.
B) After the general characteristics of the drug inhaled its active substances
Absorption: young healthy volunteers after inhalation liquid, its exclusion from the urine data show that about 33% of the inhaled drug
Reaches the systemic circulation. Chemical structure (quaternary ammonium compounds) resulting compounds and in vitro experimental data, expected
Tiotropium easily be absorbed in the gastrointestinal tract (10-15%). Tiotropium oral solution
The absolute bioavailability rate of 2-3%. In the steady state, to Respimat inhaler 5 g (microgram)
Dose 10 minutes later, the blood of patients with chronic obstructive pulmonary disease in the tiotropium highest concentration of 10.5-11.7 pg / ml, then
Rapid drop in a multi-chamber (multi-function compartment) method, the minimum steady state blood levels of the
1.49-1.68 pg / ml. This food is not expected to affect the absorption of quaternary ammonium compounds.
Distribution: The drug and serum protein binding rate of 72%, the volume of distribution (volume of distribution)
Of 32 l / kg. Not know the local concentration of the lungs, but this administration is displayed in the lungs should have a higher concentration of BPI Number: 0269-002006 On March 21
+2007 EU's SPC Version 5
March 11
Degrees. Experiments in rats showed that tiotropium can not penetrate the blood-brain barrier.
Biotransformation (biotransformation): Biological conversion rate tiotropium is very low, as evidenced by
From young healthy volunteers after intravenous injection to have 74% of the drug in order to exclude the prototype via urine .Tiotropium
Bromide is an ester, do not cut through the enzyme and alcohols (N-methylscopine) and acid compounds
(Dithienylglycolic acid), both of which are not of binding to muscarinic receptors in human liver microsomes
(Fine particles) in vitro with human liver cells, showed some drugs (less than 20% of the intravenous injection
Amount) of cytochrome P450 (cytochrome P450, CYP) to oxidation to metabolism, followed by reaction with Glutathione S
(GSH) combined into the second phase of metabolite (II phase metabolites).
Liver microsomes in vitro studies showed that the enzyme of this pathway is CYP2D6 (and 3A4) inhibitors (such as
Quinidine, ketoconazole and gestodene) are inhibited CYP2D6 and 3A4 displayed its metabolic pathways
Related enzymes responsible for the exclusion of these small portion of the drug. Even more than the therapeutic dose of tiotropium,
Will not inhibit CYP1A1,1A2,2B6,2C9,2C19,2D6,2E1 human liver microsomes or 3A.
Clear: After tiotropium via inhalation, the last phase exclude half-life between 5-6 days from the young and healthy
Those who are willing to total clearance rate after intravenous injection of 880 ml / min, the difference between individuals is 22%. Intravenous
Tiotropium mainly through the urine prototype exclude (74%). When in the form of inhalation solution, with 20.1-29.4
% Of the dose in the urine eliminated most of the remaining intestinal absorption of the drug is not excluded by the feces. Tiotropium
Bromides of creatinine renal clearance rate of more than (creatinine) of clearance, said it would actively secreted via
Excreted in the urine.
Linear / non-linear: tiotropium within the therapeutic range, either intravenously or soluble dry powder inhaler
Solution intake, its pharmacokinetics were linear relationship.
Ç special group
Elderly patients: with other drugs primarily by the kidneys of the same exclusion can be expected in older patients may be due to high
Reduced kidney function, and makes tiotropium renal clearance rate (less than 58 years of chronic obstructive pulmonary disease
The clearance rate of 326 ml in patients / min, more than 70 years of COPD patients clearance rate was 163 ml / min).
Tiotropium inhalation amount excluded from the urine, decreased from young healthy volunteers 14% suffer from chronic obstructive pulmonary disease
7% were, however, if the inter-individual differences and intra-individual differences compared, the older of the concentration in blood of patients with COPD
Degrees and no significant changes (the use of a dry powder inhaler AUC0-4h 43% increase).
Patients with impaired renal function: As with all other drugs, primarily by the kidneys of the same exclusion, whether by intravenous injection or dry
Inhalation use, will lead to kidney dysfunction drug concentration in the blood to reduce the renal clearance. Elderly patients
Who are often mild renal impairment (CLCR50-80 ml / min), will increase slightly tiotropium plasma concentration
Degree (after intravenous infusion AUC0-4h increased 39%). Impairment (CLCR <50 ml / min) in the moderate or severe renal
Chronic obstructive pulmonary disease patients, intravenous tiotropium plasma concentration will increase twice (AUC0-4h increased 82%),
Inhalation of a dry powder inhaler or in a RESPIMAT blood concentration after the solution is also the same case.
Patients with impaired liver function: liver dysfunction for tiotropium pharmacokinetics should not be affected.
Tiotropium is mainly via the kidneys excluded (in young healthy volunteers accounted for 74%), as well as by simple
Non-enzymatic ester formation fracture without drug metabolites activity.
Pediatric patients: See Dosage
Relationship D) pharmacokinetic / pharmacodynamic between
No between pharmacokinetics and pharmacodynamics direct relationship BPI number: 0269-002006 On March 21
+2007 EU's SPC Version 5
April 11
Preclinical safety data
In conventional safety pharmacology studies, multi-dose toxicity and reproductive toxicity, the observed effect may be attributed to many
To tiotropium anticholinergic effect properties. In animal experiments are usually observed reduced food intake, body
Re not increased, dry mouth and nose, tears and saliva secretion, dilated pupils and rapid heart beat. Multi-agent toxicity studies
Other related effects found for: rats and mice caused by rhinitis and epithelial changes in the nose and throat of call
Mild respiratory tract irritation, as well as prostatitis and associated protein deposition in rats occurred in the bladder with stones.
Of the pregnancy, embryonic / fetal development, birth or postnatal development affect only maternal toxicity at doses significantly beginning
Now the harmful effects of .Tiotropium bromide in rats and rabbits are not a teratogenicity. Local or systemic exposure
Changes more than five times the therapeutic exposure may lead to respiratory tract (stimulation) or genitourinary (prostatitis) of
And reproductive toxicity, genotoxicity and carcinogenicity studies of tiotropium showed no special hazard to humans
Sex.
Indications
Chronic obstructive pulmonary disease (including chronic bronchitis and emphysema) of maintenance therapy.
Dosage
The prescription drug shall use
SPIRIVA RESPIMAT recommended dose once a day, every timed by the second spraying (see "Using says
That "the use of the drug).
Elderly persons to follow the recommended dose.
Patients with impaired renal function to follow the recommended dose. But the main renal excretion of drugs via the same with others, when the
For moderate to severe renal function impairment patients need to closely monitor the condition.
Patients with impaired liver function to follow the recommended dose.
Chronic obstructive pulmonary disease does not usually occur in children .SPIRIVA RESPIMAT no children's safety and efficacy data.
Therefore not recommended for use in this age group.
Instructions
Please read and carefully use of the drug in accordance with instructions for use |
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