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曲司氯铵属于抗胆碱能类化合物，称为毒蕈碱受体拮抗剂，可松弛膀胱平滑肌，减轻导致ＯＡＢ症状的平滑肌收缩。用于治疗伴有急迫性尿失 禁症状的膀胱过度活动症的抗胆碱药物.
药品英文名
Trospium
药品别名
盐酸曲司氯铵、Trospium Hydrochloride、Sanctura
药物剂型
盐酸曲司氯铵片剂：20mg/片。20～25℃室温保存。
盐酸曲司氯铵缓释胶囊：60MG/颗。20～25℃室温保存。
药理作用
本品为季铵盐化合物，具有抗胆碱作用和解痉作用。本品作用于胆碱能神经所支配效应器上的M受体，能拮抗乙酰胆碱对M受体的作用。其副交感神经阻滞作用可引起膀胱平滑肌的舒张，使膀胱容量增加。治疗剂量下，本品对烟碱受体作用微弱。
药动学
本品口服后吸收率不足10%，平均生物利用度9.6%。给药后5～6h血药浓度达峰值(Cmax)，给药剂量从20mg增加到40mg和60mg，Cmax分别增加3倍和4倍。药时曲线下面积(AUC)随剂量呈线性变化。高脂饮食可使本品的AUC和Cmax降低70%～80%。体外研究显示，0.5～50ng/ml浓度范围内，本品血浆蛋白结合率50%～85%，本品主要分布在血浆，口服20mg的表观分布容积为395L。本品可能通过水解作用与葡萄糖醛酸结合，代谢产物占排出物的40%。本品消除半衰期约20h，85.2%经粪便排出，5.8%经肾脏排出，肾脏排出物的60%为原形药物。本品的肾脏排泄主要经肾小管分泌，严重肾功能不全患者的AUC和Cmax分别提高4.5倍和2倍，半衰期延长至33h。肝功能轻度至中度异常患者的Cmax分别升高12%和63%。
适应证
本品用于膀胱过度刺激引起的尿频、尿急、尿失禁。
禁忌证
1.对本品及其中成分过敏者禁用。
2.尿潴留、胃潴留及未控制的闭角型青光眼患者禁用。
注意事项
1.儿童用药安全性尚未评价。
2.本品过量可引起严重抗胆碱作用，有过量后引起瞳孔散大和心动过速的病例。出现药物过量应采取对症治疗和支持治疗，并监测心电图。
3.慎用：
(1)由于尿潴留的可能，有明显膀胱尿道阻塞症状的患者使用时应谨慎。
(2)本品具有抗胆碱作用，能降低胃肠道动力，胃肠道阻塞性疾病患者有胃潴留的可能，使用时应谨慎。严重便秘、溃疡性结肠炎和重症肌无力患者慎用。
(3)中度至重度肝功能不全患者慎用。
(4)只有当可能的受益高于危险时，方可在严密监护下用于已控制的闭角型青光眼患者。
(5)本品生殖毒性分级为C，只有对母体的益处高于对胎儿的危险时方可用于孕妇。
(6)本品可经大鼠乳汁分泌，尚不知本品是否经人乳汁分泌，只有当可能的受益高于对新生儿的危险时方可用于哺乳期妇女。
不良反应
本品最常见的不良反应为便秘、口干。其他不良反应包括以下几方面。
1.消化系统：口干、便秘、腹痛加剧、便秘加重、消化不良、胃肠胀气、呕吐、味觉障碍、咽干、胃炎。
2.泌尿生殖系统：尿潴留。
3.神经系统：头痛、晕厥、幻觉、躁狂。
4.全身：无力、胸痛。
5.代谢及营养疾病：有血管神经性水肿的报道。
6.心血管系统：心动过速、心悸、室上性心动过速、高血压危象。
7.皮肤：皮肤干燥、渗出性多形性红斑、过敏反应。
8.其他：眼干、视力模糊、视觉异常、横纹肌溶解。
用法用量
口服，推荐剂量为每次20mg，2次/d，空腹服用或饭前1h服用。严重肾功能损伤患者(肌酐清除率＜30ml/min)，推荐剂量为20mg/d，睡前服用。75岁以上老年患者，起始剂量为20mg/d。
药物相应作用
1.本品从肾脏排出主要经肾小管分泌作用，与其他经肾小管分泌排泄的药物(如地高辛、普鲁卡因胺、双哌雄双酯、吗啡、万古霉素、二甲双胍及替诺福韦)同时使用，有可能引起二者血药浓度的提高，应对患者进行严密监护。
2.与混合性P450抑制剂西咪替丁合用，本品的Cmax和AUC增加。
3.本品为CYP2D6和CYP3A4抑制剂，与主要经CYP2D6代谢的治疗窗较窄的药物(如氟卡尼、硫利达嗪及三环类抗抑郁药)合用时应谨慎。本品可使丙咪嗪的Cmax和AUC增加。
4.与其他抗胆碱药合用，可能加剧口干、便秘、视力模糊及其他抗胆碱症状。
5.由于本品的胃肠道动力降低作用，本品可影响其他药物的胃肠道吸收。
Sanctura XR
Generic Name: trospium chloride
Dosage Form: capsule, extended release
Indications and Usage for Sanctura XR
Sanctura XR® is a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.
Sanctura XR Dosage and Administration
The recommended dosage of Sanctura XR® is one 60 mg capsule daily in the morning. Sanctura XR® capsules should be dosed with water on an empty stomach, at least one hour before a meal.
Sanctura XR® is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) [see Warnings and Precautions (5.6), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Dosage Forms and Strengths
Sanctura XR® is supplied as 60 mg capsules (white opaque body and orange opaque cap, printed with SAN 60).
Contraindications
Sanctura XR® is contraindicated in patients with:
•urinary retention
•gastric retention
•uncontrolled narrow-angle glaucoma
•known hypersensitivity to the drug or its ingredients. Angioedema, rash and anaphylactic reaction have been reported.
Warnings and Precautions
Risk of Urinary Retention
Sanctura XR® capsules should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see Contraindications (4)].
Angioedema
Angioedema of the face, lips, tongue and/or larynx has been reported with trospium chloride. In one case, angioedema occurred after the first dose of trospium chloride. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, trospium chloride should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.
Decreased Gastrointestinal Motility
Sanctura XR® should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention [see Contraindications (4)]. Sanctura XR®, like other antimuscarinic agents, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis, intestinal atony and myasthenia gravis.
Controlled Narrow-angle Glaucoma
In patients being treated for narrow-angle glaucoma, Sanctura XR® should only be used if the potential benefits outweigh the risks, and in that circumstance only with careful monitoring [see Contraindications (4)].
Central Nervous System Effects
Sanctura XR® and SANCTURA® are associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6.2)]. A variety of CNS anticholinergic effects have been reported, including dizziness, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Sanctura XR® affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
Patients with Severe Renal Impairment
Sanctura XR® is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) [see Dosage and Administration (2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Alcohol Interaction
Alcohol should not be consumed within 2 hours of Sanctura XR® administration. In addition, patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The data described below reflect exposure to Sanctura XR® capsules in 578 patients for 12 weeks in two Phase 3 double-blind, placebo controlled trials (n=1165). These studies included overactive bladder patients of ages 21 to 90 years, of which 86% were female and 85% were Caucasian. Patients received 60 mg daily doses of Sanctura XR®. Patients in these studies were eligible to continue treatment with Sanctura XR® 60 mg for up to one year. From both these controlled trials combined, 769 and 238 patients received treatment with Sanctura XR® for at least 24 and 52 weeks, respectively.
There were 157 (27.2%) Sanctura XR® patients and 98 (16.7%) placebo patients who experienced one or more double-blind treatment-emergent adverse events (TEAEs) that were assessed by the investigator as at least possibly related to study medication. The most common TEAEs were dry mouth and constipation which, when reported, commonly occurred early in treatment (often within the first week). In the two Phase 3 studies, constipation, dry mouth, and urinary retention led to discontinuation in 1%, 0.7%, and 0.5% of patients treated with Sanctura XR® 60 mg daily, respectively. In the placebo group, there were no discontinuations due to dry mouth or urinary retention and one due to constipation.
The incidence of serious adverse events was similar among patients receiving Sanctura XR® and patients receiving placebo. No treatment-emergent serious adverse events in either treatment group were judged by the investigators as being possibly related to the study medication.
Table 1 lists those treatment emergent adverse events from the trials that were assessed by the investigator as possibly related to study medication, reported in at least 1% of Sanctura XR® patients, and were more common for the Sanctura XR® group than for placebo.
Additional adverse events reported in less than 1% of Sanctura XR® treated patients and more common for Sanctura XR® than placebo, judged by the investigator at least possibly related to treatment were: vision blurred, feces hard, back pain, somnolence, urinary retention, and dry skin.
Table 2 lists all treatment-emergent adverse events for the trials reported in at least 2% of all Sanctura XR® patients and more common for the Sanctura XR® group than for placebo without regard to the investigator's judgment on drug relatedness.
Additional adverse events reported in less than 2% of Sanctura XR® treated patients and twice as frequent for Sanctura XR® compared to placebo, regardless of reported relationship to treatment were: tachycardia, dry eyes, abdominal pain, dyspepsia, abdominal distension, constipation aggravated, nasal dryness, and rash.
In the open-label treatment phase, the most common TEAEs reported in the 769 patients with at least 6 months exposure to Sanctura XR® were: constipation, and dry mouth. Urinary tract infection and rash was also reported in several patients, including one of each judged by the investigator to be possibly related to treatment. Several adverse events were reported as severe in the open-label treatment phase, including one urinary tract infection, two urinary retention events, and one aggravated constipation.
Post-marketing Experience
The following adverse reactions have been identified during post-approval use of trospium chloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal – gastritis; Cardiovascular – palpitations, supraventricular tachycardia, chest pain, syncope, “hypertensive crisis”; Immunological – Stevens-Johnson syndrome, anaphylactic reaction, angioedema; Nervous System – dizziness, confusion, vision abnormal, hallucinations, somnolence, and delirium; Musculoskeletal – rhabdomyolysis; General – rash.
Drug Interactions
Trospium is metabolized by ester hydrolysis and excreted by the kidneys through a combination of tubular secretion and glomerular filtration. Based on in vitro data, no clinically relevant metabolic drug-drug interactions are anticipated with Sanctura XR®. However, some drugs which are actively secreted by the kidney may interact with Sanctura XR® by competing for renal tubular secretion.
The concomitant use of Sanctura XR® with other antimuscarinic agents that produce dry mouth, constipation, and other anticholinergic effects may increase the frequency and/or severity of such effects. Sanctura XR® may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.
Digoxin
Concomitant use of trospium chloride 20mg twice daily and digoxin did not affect the pharmacokinetics of either drug [see Clinical Pharmacology (12.3)].
Antacid
While the systemic exposure of trospium on average was comparable with and without antacid containing aluminum hydroxide and magnesium carbonate, 5 out of 11 individuals in a drug interaction study demonstrated either an increase or decrease in trospium exposure, in presence of antacid. The clinical relevance of these findings is not known [see Clinical Pharmacology (12.3)].
Metformin
Co-administration of 500 mg metformin immediate release tablets twice daily reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC(0-24) and by 34% for mean Cmax. The effect of a decrease in trospium exposure on the efficacy of Sanctura XR® is unknown. The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg Sanctura XR® once daily under fasted condition. The effect of metformin at higher doses on trospium PK is unknown [see Clinical Pharmacology (12.3)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Teratogenic Effects
Pregnancy Category C: There are no adequate and well-controlled studies of Sanctura XR® in pregnant women. Sanctura XR® should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during Sanctura XR® treatment are encouraged to contact their physician.
Trospium chloride was not teratogenic at statistically significant levels in rats or rabbits administered doses up to 200 mg/kg/day. This corresponds to systemic exposures up to approximately 16 and 32 times, respectively (based on AUC), the clinical exposure at the maximum recommended human dose (MRHD) of 60 mg. However, in rabbits, one fetus in each of the three treated dose groups (1, 1, and 32 times the MRHD) demonstrated multiple malformations, including umbilical hernia and skeletal malformations. A no effect level for maternal and fetal toxicity was observed at levels approximately equivalent to the clinical exposure at the MRHD (20 mg/kg/day in rats and rabbits). No developmental toxicity was observed in the offspring of female rats exposed pre- and post-natally to up to 200 mg/kg/day.
Labor and Delivery
The effect of Sanctura XR® capsules on labor and delivery is unknown.
Nursing Mothers
Trospium chloride (2 mg/kg orally and 50 mcg/kg intravenously) was excreted, to a limited extent (less than 1%), into the milk of lactating rats (primarily as parent compound). It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, Sanctura XR® should be used during lactation only if the potential benefit justifies the potential risk.
Pediatric Use
The safety and effectiveness of Sanctura XR® in pediatric patients have not been established.
Geriatric Use
Of 1165 patients in Phase 3 clinical studies of Sanctura XR®, 37% (n=428) were ages 65 and over, while 12% (n=143) were ages 75 and over.
No overall differences in effectiveness were observed between those subjects aged 65 and over and younger subjects. In Sanctura XR® subjects ages 65 and over compared to younger subjects, the following adverse reactions were reported at a higher incidence: dry mouth, constipation, abdominal pain, dyspepsia, urinary tract infection and urinary retention. In subjects ages 75 and over, three reported a fall and in one of them a relationship to the event could not be excluded.
Renal Impairment
Severe renal impairment (creatinine clearance less than 30 mL/minute) may significantly alter the disposition of Sanctura XR®. In a study of immediate-release trospium chloride, 4.2-fold and 1.8-fold increases in mean AUC(0-∞) and Cmax, respectively, were detected in patients with severe renal impairment. Use of Sanctura XR® is not recommended in patients with severe renal impairment [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. The pharmacokinetics of trospium chloride have not been studied in patients with creatinine clearance ranging from 30-80 mL/min.
Trospium is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function.
Hepatic Impairment
There is no information regarding the effect of severe hepatic impairment on exposure to Sanctura XR®. In a study of patients with mild and with moderate hepatic impairment, given 40 mg of immediate-release trospium chloride, mean Cmax increased 12% and 63%, respectively, and mean AUC(0-∞) decreased 5% and 15%, respectively, compared to healthy subjects. The clinical significance of these findings is unknown. Caution is advised, however, when administering Sanctura XR® to patients with moderate to severe hepatic impairment.
Overdosage
Overdosage with antimuscarinic agents, including Sanctura XR®, can result in severe antimuscarinic effects. Supportive treatment should be provided according to symptoms. In the event of overdosage, ECG monitoring is recommended.
Sanctura XR Description
Sanctura XR® is an extended-release formulation of trospium chloride, a quaternary ammonium compound with the chemical name of Spiro [8-azoniabicyclo[3.2.1]octane-8,1'-pyrrolidinium], 3-[(hydroxydiphenylacetyl)oxy]-, chloride, (1α, 3β, 5α). The empirical formula of trospium chloride is C25H30ClNO3 and its molecular weight is 427.97. The structural formula of trospium chloride is represented below:
Trospium chloride is a fine, colorless to slightly yellow, crystalline solid. The compound's solubility in water is approximately 1 g/2 mL.
Sanctura XR® capsules contain 60 mg of trospium chloride, a muscarinic antagonist, for oral administration. Each capsule also contains the following inactive ingredients: sugar spheres, methacrylic acid copolymer, ethyl cellulose, hydroxypropyl methylcellulose, triethyl citrate, talc, and Opadry® white.
Sanctura XR - Clinical Pharmacology
Mechanism of Action
Trospium chloride is an antispasmodic, antimuscarinic agent.
Trospium chloride antagonizes the effect of acetylcholine on muscarinic receptors in cholinergically innervated organs including the bladder. Its parasympatholytic action reduces the tonus of smooth muscle in the bladder.
In vitro receptor binding studies have demonstrated the selectivity of trospium chloride for muscarinic over nicotinic receptors, and similar affinity for the M2 and M3 muscarinic receptor subtypes. M2 and M3 receptors are found in the bladder and may play a role in the pathogenesis of overactive bladder.
Pharmacodynamics
Placebo-controlled studies assessing the impact on urodynamic variables of an immediate-release formulation of trospium chloride were conducted in patients with conditions characterized by involuntary detrusor contractions. The results demonstrated that trospium chloride increases maximum cystometric bladder capacity and volume at first detrusor contraction.
Electrophysiology
The effect of 20 mg twice daily and up to 100 mg twice daily of an immediate-release formulation of trospium chloride on QT interval was evaluated in a single-blind, randomized, placebo and active (moxifloxacin 400 mg daily) controlled, 5-day parallel trial in 170 male and female healthy volunteer subjects aged 18 to 45 years. The QT interval was measured over a 24-hour period at steady state. Trospium chloride was not associated with an increase in individual corrected (QTcI) or Fridericia corrected (QTcF) QT interval at any time during steady state measurement, while moxifloxacin was associated with a 6.4 msec increase in QTcF.
In this study, asymptomatic, non-specific T-wave inversions were observed more often in subjects receiving trospium chloride than in subjects receiving moxifloxacin or placebo following five days of treatment. The clinical significance of T-wave inversion in this study is unknown. This finding was not observed during routine safety monitoring in overactive bladder patients from 2 placebo-controlled clinical trials in 591 patients treated with 20 mg twice daily of immediate-release trospium chloride, nor was it observed in 2 placebo-controlled clinical trials in 578 patients treated with Sanctura XR® capsules.
Also in this study, the immediate-release formulation of trospium chloride was associated with an increase in heart rate that correlated with increasing plasma concentration, with a mean elevation in heart rate compared to placebo of 9 beats per minute for the 20 mg dose and of 18 beats per minute for the 100 mg dose. In the two Phase 3 Sanctura XR® trials the mean increase in heart rate compared to placebo was approximately 3 beats per minute in both studies.
Pharmacokinetics
Absorption: Mean absolute bioavailability of a 20 mg immediate-release dose is 9.6% (range 4.0-16.1%). Following a single 60 mg dose of Sanctura XR®, peak plasma concentration (Cmax) of 2.0 ng/mL occurred 5.0 hours post dose. By contrast, following a single 20 mg dose of an immediate-release formulation of trospium chloride, Cmax was 2.7 ng/mL.
Effect of Food: Administration of Sanctura XR® capsules immediately after a high (50%) fat-content meal reduced the oral bioavailability of trospium chloride by 35% for AUC(0-Tlast) and by 60% for Cmax. Other pharmacokinetic parameters such as Tmax and t½ were unchanged in the presence of food.
A summary of mean (± standard deviation) pharmacokinetic parameters for a single dose of 60 mg Sanctura XR® is provided in Table 3.
Administration of Sanctura XR® capsules immediately after a high (50%) fat-content meal reduced the oral bioavailability of trospium chloride by 35% for AUC(0-Tlast) and by 60% for Cmax. Other pharmacokinetic parameters such as Tmax and t½ were unchanged in the presence of food. Coadministration with antacid had inconsistent effects on the oral bioavailability of Sanctura XR®.
Distribution: Protein binding ranged from 50 to 85%, depending upon the assessment method used, when a range of concentration levels of trospium chloride (0.5-50 mcg/L) were incubated in vitro with human serum.
The ratio of 3H-trospium chloride in plasma to whole blood was 1.6:1. This ratio indicates that the majority of 3H- trospium chloride is distributed in plasma.
Trospium chloride is widely distributed, with an apparent volume of distribution >600 L.
Metabolism: The metabolic pathway of trospium in humans has not been fully defined. Of the dose absorbed following oral administration, metabolites account for approximately 40% of the excreted dose. The major metabolic pathway of trospium is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. CYP P450 does not contribute significantly to the elimination of trospium. Data taken from in vitro studies of human liver microsomes investigating the inhibitory effect of trospium on seven CYP P450 isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) suggest a lack of inhibition at clinically relevant concentrations.
Excretion: The plasma half-life for trospium following oral administration of Sanctura XR® is approximately 35 hours. After oral administration of an immediate-release formulation of 14C-labeled trospium chloride, a majority of the dose (85.2%) was recovered in feces and a smaller amount (5.8% of the dose) was recovered in urine. Of the radioactivity excreted into the urine, 60% was unchanged trospium.
The mean renal clearance for trospium (29.07 L/hour) is 4-fold higher than average glomerular filtration rate, indicating that active tubular secretion is a major route of elimination. There may be competition for elimination with other compounds that are also renally eliminated [see Drug Interactions (7)].
Drug Interactions
Digoxin: Concomitant use of 20 mg SANCTURA® (trospium chloride immediate release) twice daily at steady state and a single dose of 0.5 mg digoxin in a crossover study with 40 male and female subjects did not affect the pharmacokinetics of either drug.
Antacid: A drug interaction study was conducted to evaluate the effect of an antacid containing aluminum hydroxide and magnesium carbonate on the pharmacokinetics of Sanctura XR® (n=11). While the systemic exposure of trospium on average was comparable with and without antacid, 5 individuals demonstrated either an increase or decrease in trospium exposure, in presence of antacid.
Metformin: A drug interaction study was conducted in which Sanctura XR® 60 mg once daily was co-administered with Glucophage® (metformin hydrochloride) 500 mg twice daily under steady-state conditions in 44 healthy subjects. Co-administration of 500 mg metformin immediate release tablets twice daily reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC0-24 and by 34% for mean Cmax. The effect of decrease in trospium exposure on the efficacy of Sanctura XR® is unknown. The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg Sanctura XR® once daily under fasted condition. The effect of metformin at higher doses on trospium PK is unknown.
Specific Populations
Age: In a phase 3 clinical trial of Sanctura XR®, the observed plasma trospium concentrations were similar in older (greater than or equal to 65 years) and younger (less than 65 years) OAB patients.
Pediatric: The pharmacokinetics of Sanctura XR® were not evaluated in pediatric patients.
Race: Pharmacokinetic differences due to race have not been studied.
Gender: Gender differences in pharmacokinetics of Sanctura XR® have not been formally assessed. Data from healthy subjects suggests lower exposure in males compared to females.
Hepatic Impairment: There is no information regarding the effect of severe hepatic impairment on exposure to Sanctura XR®. In a study of patients with mild (Child-Pugh score 5-6) and with moderate (Child-Pugh score 7-8) hepatic impairment, given 40 mg of immediate-release trospium chloride, mean Cmax increased 12% and 63% respectively, and mean AUC(0-∞) decreased 5% and 15%, respectively, compared to healthy subjects.
Renal Impairment: The pharmacokinetics of Sanctura XR® in patients with severe renal impairment has not been evaluated. In a study of an immediate-release formulation of trospium chloride, 4.2-fold and 1.8-fold increases in mean AUC(0–∞) and Cmax, respectively, were detected in patients with severe renal impairment (creatinine clearance less than 30 mL/minute), compared with healthy subjects, along with the appearance of an additional elimination phase with a long half-life (~33 hours vs. 18 hours). Use of Sanctura XR® is not recommended in patients with severe renal impairment [see Dosage and Administration (2)]. The pharmacokinetics of trospium chloride have not been studied in people with creatinine clearance ranging from 30-80 mL/min.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Carcinogenicity studies with trospium chloride were conducted in mice and rats for 78 weeks and 104 weeks, respectively, at maximally tolerated doses. No evidence of a carcinogenic effect was found in either mice or rats administered up to 200 mg/kg/day (approximately 1 and 16 times, respectively (based on AUC), the expected clinical exposure levels at the maximum recommended human dose (MRHD) of 60 mg.
Mutagenesis: Trospium chloride was not mutagenic nor genotoxic in tests in vitro in bacteria (Ames test) and mammalian cells (L5178Y mouse lymphoma and CHO cells) or in vivo in the mouse micronucleus test.
Impairment of Fertility: No evidence of impaired fertility was observed in rats administered doses up to 200 mg/kg/day (about 16 times the expected clinical exposure at the MRHD, based on AUC).
Clinical Studies
Sanctura XR® was evaluated for the treatment of patients with overactive bladder who had symptoms of urinary frequency, urgency and urge urinary incontinence in two 12-week, randomized, double-blind, placebo-controlled studies. For both studies, entry criteria required the presence of urge incontinence (predominance of urge), at least one incontinence episode per day, and 10 or more micturitions (voids) per day (assessed by 3-day urinary diary). Medical history and data from the baseline urinary diary confirmed the diagnosis. Approximately 88% of the patients enrolled completed the 12-week studies. The mean age was 60 years, and the majority of patients were female (84%) and Caucasian (86%).
The co-primary endpoints in the trials were the mean change from baseline to Week 12 in number of voids/24 hours (reductions in urinary frequency) and the mean change from baseline to Week 12 in number of incontinence episodes/24 hours. Secondary endpoints included mean change from baseline to Week 12 in volume per void.
Study 1 included 592 patients in both Sanctura XR® 60 mg and placebo groups. As illustrated in Table 4 and Figures 2 and 3, Sanctura XR® demonstrated statistically significantly (p<0.01) greater reductions in the urinary frequency and incontinence episodes, and increases in void volume when compared to placebo starting at Week 1 and maintained through Weeks 4 and 12
Study 2 included 543 patients in both Sanctura XR® 60 mg and placebo groups and was identical in design to Study 1. As illustrated in Table 5 and Figures 4 and 5, Sanctura XR® capsules demonstrated statistically significantly (p<0.01) greater reductions in urinary frequency and incontinence episodes, and increases in void volume when compared to placebo at Weeks 4 and 12. However, at Week 1, statistically significant reductions were seen in urinary incontinence episodes and volume void only.
How Supplied/Storage and Handling
Sanctura XR® is supplied as 60 mg capsules (white opaque body and orange opaque cap, printed with SAN 60): 60 mg capsule, 30 count, HDPE bottle: NDC 0023-9350-30
Store at controlled room temperature 20° to 25°C (68° to 77°F). Excursion permitted at 15° to 30°C (see USP).
附件:
20126518383320.PDF
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产地国家: 美国
原产地英文商品名:
SANCTURA XR CAP SA 60MG/CAP 30CAPS/BOTTLE
原产地英文药品名:
TROSPIUM CHLORIDE
中文参考商品译名:
SANCTURA XR缓释胶囊 60毫克/胶囊 30胶囊/瓶
中文参考药品译名:
曲司氯铵
生产厂家中文参考译名:
艾尔建
生产厂家英文名:
ALLERGAN
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产地国家: 美国
原产地英文商品名:
SANCTURA 20MG/TAB 60TABS/BOTTLE
原产地英文药品名:
TROSPIUM CHLORIDE
中文参考商品译名:
SANCTURA 20毫克/片 60片/瓶
中文参考药品译名:
曲司氯铵
生产厂家中文参考译名:
艾尔建
生产厂家英文名:
ALLERGAN
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