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癫痫是最常见的严重神经性疾病，有2种或更多种原发性惊厥，其危害到全球大约5000万人。癫痫的惊厥是由神经元的不正常发电引起，其原因可能包括头部外伤、酒精、脑肿病或脑血管疾病等。 抗癫痫药是癫痫治疗的主要办法，通过限制神经元的重复放电来阻断电信号的扩散。虽然单独用药是优选，但是许多患者也许需要多种药物，尽管是联合治疗，而优化的惊厥控制治疗效果并没有保证。过去几年里已上市了多个抗癫痫药，噻加宾(tiagabine，Gabitril)是第一个氨基酪酸(GABA)摄取抑制剂。 噻加宾的化学名称为(R)-(-)-N-[4,4-二(3-甲基-2-噻吩基)-1-丁基-3-烯]哌啶-3-甲酸盐酸盐。其适应证为联合治疗癫痫部分发作，具有或不具有继发的全身大发作，并且是至少一种抗癫痫药的优化剂型无法控制的癫痫。本品由Novo Nordisk 公司开发，1996年首先在丹麦和法国上市，1997年在美国。至今已在20多个国家上市。1999年在USA销售2000万美元，2003 年就超过1亿美元。2003年其专利到期，在中国已有进口药品申请临床， 但尚未在中国上市。 作用特点 (1) 噻加宾是一新型作用模式的抗癫痫药，为第一个专一的GABA再摄取抑制剂。 (2) 与安慰剂相比，对于顽固性癫痫，26%病因性患者的发作次数减少50% 或更多；60%强直性阵挛发作患者的发作次数减少50%或更多。 (3) 总的来说本品耐受性好，不良反应温和，至多也是很适度的，通常也是瞬间的。长期服用没有其他抗癫痫药的耐受性或药物动力学参数的改变。与其它药物相比，适合长期服用。 (4) 肝中能诱导抗癫痫药的酶，能增强本品的代谢，减少血清浓度。
治疗花费比较 药物 本品为3-哌啶甲酸的合成衍生物，是GABA摄取的强抑制剂，GABA是大脑中主要神经递质，已显示其缺乏将会引起惊厥。GABA能增加氯离子的内流，从而降低膜引起重复极化和高极化的潜力，借此抑制神经冲动的传导。本品可增强GABA能神经的抑制作用，尤其是通过减少GABA的摄取，主要选择性作用于摄取载体蛋白GAT-1。已经探明神经元和灰质的GABA摄取蛋白(GAT) 底物明显不同于那些突触后GABA受体的底物，所以GABA摄取转运蛋白选择性抑制剂可避免系统不良反应。因此与其他抗癫痫药相比，GABA摄取抑制剂更有前景。 药代动力学 本品口服后能被完全迅速吸收，口服后约30～90分钟内血浆药物浓度达最高峰，生物利用度为90%～95%。食物可降低吸收速度，但不影响吸收量。本品的药代动力学是线性的，半衰期对非酶诱导者是7～9小时，对酶诱导者是2～3小时。由于短的半衰期需要一日多次服用，控释剂也将是很有用的。 本品的蛋白结合率为96%，在肝中被广泛代谢，少于1%的原型从尿中排泄。体外研究提示代谢主要通过细胞色素P4503A氧化代谢过程，未检测到活性代谢物。在健康志愿者中涉及到多种剂量的研究并未指明本品可诱导或抑制肝脏微粒体酶系统。 临床研究 在临床研究中说明的剂量是作为噻加宾盐酸盐，在英国其剂量经一个0.91系数换算成游离碱。 临床数据资料来自5项多中心的随机双盲安慰剂对照研究，涉及12～72岁难治性部分发作患者951例。在双盲交换研究中，本品显著减少复杂性部分发作和继发性大发作。与安慰剂相比，90例患者进入交换阶段，78例完成这项研究。 在为期12周的研究中，154例成年患者随机接受本品一日3次，每次10mg（77例）或安慰剂（77例），本品组21例（27%）退出，安慰剂组8例（10%）退出。按治疗意图分析，结果显示，对所有部分发作或简单部分发作者，本品治疗4周内的发作率显著减少（P<0.05），发作次数减少量大于50%，而安慰剂组无显示差异（分别为14%对 6%）。 一项为期20周的剂量反应研究中，297例患者随机接受本品16，32或56mg或安慰剂，247例完成了双盲研究，54例退出。按治疗意图分析，主要终点是4周内的复杂部分发作频率的平均变化。与安慰剂相比，本品32和56mg组具有统计学意义的发作率显著减少。从基线上看复杂部分发作频率的平均变化，安慰剂组为-0.7，本品32mg组(P = 0.03)为 -2.2，本品56mg组(P <0.03)为 -2.8。本品32和56mg组20% 和29%患者在复杂部分发作率方面分别下降50%，而安慰组为4% (分别 为P = 0.02 和 P < 0.01)。 在一项为期16周的研究中，318例患者随机接受本品一日2次，每次16mg(106例)，一日4次，每次8mg(107例)，或安慰剂一日4次。271例完成了研究，47例退出。按治疗意图分析，4周内复杂部分发作频率16mg组从基线的8.4次平均减少1.6次(P=-0.06)；8mg组平均减少1.2次 (P=0.02)。部分发作观察到下降50%的16mg组为31%，8mg 组为27%，安慰剂组为10% (P £ 0.01)。 这5项研究结果分析显示，当用于辅助治疗时，本品优于安慰剂。发作频率下降50%的患者比例，与安慰剂相比，对复杂部分发作是 27%对13%，对简单部分发作为30% 对10%；对继发性强直阵痉挛性大发为40%对30%。 适应证 本品被推荐用于连续联合治疗成人和12岁以上儿童的部分发作，具有或不具有继发性大发作，并且用至少一种其它抗癫药的优化剂量不能控制的发作。 不良反应 来自5项安慰剂对照研究的安全性资料显示绝大数常见的不良反应为眩晕（与安慰剂相比，30% 对13%）、乏力（24% 对12%）、神经质（12% 对3%）、压抑 （5% 对1%）等。停用本品的主要原因：眩晕（3%），乏力（3%），磕睡（2%）和运动失调（2%）。未见本品严重或非常严重的特异性事件报道。 禁忌证 对本品或其辅料过敏者；12岁以下儿童；孕妇，哺乳期妇女及肝功能严重受损者禁用。 药物相互作用 肝酶诱导剂（苯妥英，卡马西平，苯巴比酮和扑米酮）可增强本品代谢，与这些药物共同使用时，本品在血浆中的浓度也许可以减少1.5 ～3个单位。而本品在临床上并不能显著影响这些药物的血浆浓度：苯妥英、卡马西平、苯巴比妥、华法林、地高辛、茶碱、西咪替丁和口服避孕药。本品可使丙戊酸的血浆浓度减少约10%，然而临床上并不认为这很重要，剂量增加也没有必要。
【原产地英文商品名】GABITRIL 12mg/tablet 30tablets/bottle
GABITRIL®; (tiagabine hydrochloride) Tablets DRUG DESCRIPTION Inactive Ingredients In addition, individual tablets contain: -------------------------------------------- INDICATIONS -------------------------------------------- GABITRIL (tiagabine HCl) is recommended as adjunctive therapy for the treatment of partial seizures in patients 12 years and older. The following dosing recommendations apply to all patients taking GABITRIL: Induced Adults and Adolescents 12 Years or Older In adolescents 12 to 18 years old, GABITRIL should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of GABITRIL may be increased by 4 mg at the beginning of Week 2. Thereafter, the total daily dose may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or up to 32 mg/day. The total daily dose should be given in divided doses two to four times daily. Doses above 32 mg/day have been tolerated in a small number of adolescent patients for a relatively short duration. In adults, GABITRIL should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of GABITRIL may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or, up to 56 mg/day. The total daily dose should be given in divided doses two to four times daily. Doses above 56 mg/day have not been systematically evaluated in adequate and wellcontrolled clinical trials. Non-Induced Adults and Adolescents 12 Years or Older Following a given dose of GABITRIL, the estimated plasma concentration in the non-induced patients is more than twice that in patients receiving enzyme-inducing agents. Use in noninduced patients requires lower doses of GABITRIL. These patients may also require a slower titration of GABITRIL compared to that of induced patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS, General, Use in Non- Induced Patients). -------------------------------------------- Recommended Storage: Store tablets at controlled room temperature, between 20-25°C (68- 77°F). See USP. Protect from light and moisture. -------------------------------------------- Approximately 21% of the 2531 patients who received GABITRIL in clinical trials of epilepsy discontinued treatment because of an adverse event. The adverse events most commonly associated with discontinuation were dizziness (1.7%), somnolence (1.6%), depression (1.3%), confusion (1.1%), and asthenia (1.1%). In Studies 1 and 2 (U.S. studies), the double-blind, placebo-controlled, parallel-group, add-on studies, the proportion of patients who discontinued treatment because of adverse events was 11% for the group treated with GABITRIL and 6% for the placebo group. The most common adverse events considered the primary reason for discontinuation were confusion (1.2%), somnolence (1.0%), and ataxia (1.0%). Adverse Event Incidence in Controlled Clinical Trials The prescriber should be aware that these figures, obtained when GABITRIL was added to concurrent antiepilepsy drug therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied. Other events reported by 1% or more of patients treated with GABITRIL but equally or more frequent in the placebo group were: accidental injury, chest pain, constipation, flu syndrome, rhinitis, anorexia, back pain, dry mouth, flatulence, ecchymosis, twitching, fever, amblyopia, conjunctivitis, urinary tract infection, urinary frequency, infection, dyspepsia, gastroenteritis, nausea and vomiting, myalgia, diplopia, headache, anxiety, acne, sinusitis, and incoordination. Study 1 was a dose-response study including doses of 32 mg and 56 mg. Table 6 shows adverse events reported at a rate of ≥ 5% in at least one GABITRIL group and more frequent than in the placebo group. Among these events, depression, tremor, nervousness, difficulty with concentration/attention, and perhaps asthenia exhibited a positive relationship to dose. Other Adverse Events Observed During All Clinical Trials Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. -------------------------------------------- The drug interaction data described in this section were obtained from studies involving either healthy subjects or patients with epilepsy. Effects of GABITRIL on other Antiepilepsy Drugs (AEDs) Carbamazepine: Tiagabine had no effect on the steady-state plasma concentrations of carbamazepine or its epoxide metabolite in patients with epilepsy. Valproate: Tiagabine causes a slight decrease (about 10%) in steady-state valproate concentrations. Phenobarbital or Primidone: No formal pharmacokinetic studies have been performed examining the addition of tiagabine to regimens containing phenobarbital or primidone. The addition of tiagabine in a limited number of patients in three well-controlled studies caused no systematic changes in phenobarbital or primidone concentrations when compared to placebo. Effects of other Antiepilepsy Drugs (AEDs) on GABITRIL Phenytoin: Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking phenytoin with or without other enzyme-inducing AEDs. Phenobarbital (Primidone): Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking phenobarbital (primidone) with or without other enzyme-inducing AEDs. Valproate: The addition of tiagabine to patients taking valproate chronically had no effect on tiagabine pharmacokinetics, but valproate significantly decreased tiagabine binding in vitro from 96.3 to 94.8%, which resulted in an increase of approximately 40% in the free tiagabine concentration. The clinical relevance of this in vitro finding is unknown. Interaction of GABITRIL with Other Drugs Theophylline: A single 10 mg dose of tiagabine did not affect the pharmacokinetics of theophylline at steady state. Warfarin: No significant differences were observed in the steady-state pharmacokinetics of Rwarfarin or S-warfarin with the addition of tiagabine given as a single dose. Prothrombin times were not affected by tiagabine. Digoxin: Concomitant administration of tiagabine did not affect the steady-state pharmacokinetics of digoxin or the mean daily trough serum level of digoxin. Ethanol or Triazolam: No significant differences were observed in the pharmacokinetics of triazolam (0.125 mg) and tiagabine (10 mg) when given together as a single dose. The pharmacokinetics of ethanol were not affected by multiple-dose administration of tiagabine. Tiagabine has shown no clinically important potentiation of the pharmacodynamic effects of triazolam or alcohol. Because of the possible additive effects of drugs that may depress the nervous system, ethanol or triazolam should be used cautiously in combination with tiagabine. Oral Contraceptives: Multiple dose administration of tiagabine (8 mg/day monotherapy) did not alter the pharmacokinetics of oral contraceptives in healthy women of child-bearing age. Antipyrine: Antipyrine pharmacokinetics were not significantly different before and after tiagabine multiple-dose regimens. This indicates that tiagabine does not cause induction or inhibition of the hepatic microsomal enzyme systems responsible for the metabolism of antipyrine. Interaction of GABITRIL with Highly Protein Bound Drugs -------------------------------------------- The GABITRIL dosing recommendations in current labeling for treatment of epilepsy were based on use in patients with partial seizures 12 years of age and older, most of whom were taking enzyme-inducing antiepileptic drugs (AEDs; e.g., carbamazepine, phenytoin, primidone and phenobarbital) which lower plasma levels of GABITRIL by inducing its metabolism. Use of GABITRIL without enzyme-inducing antiepileptic drugs results in blood levels about twice those attained in the studies on which current dosing recommendations are based (see DOSAGE AND ADMINISTRATION). Safety and effectiveness of GABITRIL have not been established for any indication other than as adjunctive therapy for partial seizures in adults and children 12 years and older. In nonepileptic patients who develop seizures while on GABITRIL treatment, GABITRIL should be discontinued and patients should be evaluated for an underlying seizure disorder. Seizures and status epilepticus are known to occur with GABITRIL overdosage (see OVERDOSAGE). Suicidal Behavior and Ideation Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Anyone considering prescribing GABITRIL or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Withdrawal Seizures Cognitive/Neuropsychiatric Adverse Events Patients with a history of spike and wave discharges on EEG have been reported to have exacerbations of their EEG abnormalities associated with these cognitive/neuropsychiatric events. This raises the possibility that these clinical events may, in some cases, be a manifestation of underlying seizure activity (see PRECAUTIONS, Laboratory Tests, EEG). In the documented cases of spike and wave discharges on EEG with cognitive/neuropsychiatric events, patients usually continued tiagabine, but required dosage adjustment. Additionally, there have been postmarketing reports of patients who have experienced cognitive/neuropsychiatric symptoms, some accompanied by EEG abnormalities such as generalized spike and wave activity, that have been reported as nonconvulsant status epilepticus. Some reports describe recovery following reduction of dose or discontinuation of GABITRIL. Status Epilepticus Sudden Unexpected Death In Epilepsy (SUDEP) This represents an estimated incidence of 0.0026 deaths per patient-year. This rate is within the range of estimates for the incidence of sudden and unexpected deaths in patients with epilepsy not receiving GABITRIL (ranging from 0.0005 for the general population with epilepsy, 0.003 to 0.004 for clinical trial populations similar to that in the clinical development program for GABITRIL, to 0.005 for patients with refractory epilepsy). The estimated SUDEP rates in patients receiving GABITRIL are also similar to those observed in patients receiving other antiepilepsy drugs, chemically unrelated to GABITRIL, that underwent clinical testing in similar populations at about the same time. This evidence suggests that the SUDEP rates reflect population rates, not a drug effect. -------------------------------------------- Generalized Weakness Binding in the Eye and Other Melanin-Containing Tissues Use in Hepatically-Impaired Patients Serious Rash Laboratory Tests Clinical Chemistry and Hematology EEG Carcinogenesis, Mutagenesis, Impairment of Fertility Mutagenesis Impairment of Fertility Pregnancy An increased incidence of malformed fetuses (various craniofacial, appendicular, and visceral defects) and decreased fetal weights were observed following oral administration of 100 mg/kg/day to pregnant rats during the period of organogenesis. This dose is approximately 16 times the maximum recommended human dose (MRHD) of 56 mg/day, based on body surface area (mg/m²). Maternal toxicity (transient weight loss/reduced maternal weight gain during gestation) was associated with this dose, but there is no evidence to suggest that the teratogenic effects were secondary to the maternal effects. No adverse maternal or embryo-fetal effects were seen at a dose of 20 mg/kg/day (3 times the MRHD on a mg/m² basis). Decreased maternal weight gain, increased resorption of embryos and increased incidences of fetal variations, but not malformations, were observed when pregnant rabbits were given 25 mg/kg/day (8 times the MRHD on a mg/m² basis) during organogenesis. The no effect level for maternal and embryo-fetal toxicity in rabbits was 5 mg/kg/day (equivalent to the MRHD on a mg/m² basis). When female rats were given tiagabine 100 mg/kg/day during late gestation and throughout parturition and lactation, decreased maternal weight gain during gestation, an increase in stillbirths, and decreased postnatal offspring viability and growth were found. There are no adequate and well-controlled studies in pregnant women. Tiagabine should be used during pregnancy only if clearly needed. To provide additional information regarding the effects of in utero exposure to GABITRIL, physicians are advised to recommend that pregnant patients taking GABITRIL enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website in Nursing Mothers Pediatric Use Geriatric Use -------------------------------------------- From post-marketing experience, there have been no reports of fatal overdoses involving GABITRIL alone (doses up to 720 mg), although a number of patients required intubation and ventilatory support as part of the management of their status epilepticus. Overdoses involving multiple drugs, including GABITRIL, have resulted in fatal outcomes. Symptoms most often accompanying GABITRIL overdose, alone or in combination with other drugs, have included: seizures including status epilepticus in patients with and without underlying seizure disorders, nonconvulsive status epilepticus, coma, ataxia, confusion, somnolence, drowsiness, impaired speech, agitation, lethargy, myoclonus, spike wave stupor, tremors, disorientation, vomiting, hostility, and temporary paralysis. Respiratory depression was seen in a number of patients, including children, in the context of seizures. Management of Overdose -------------------------------------------- |
盐酸噻加宾片Gabitril (Tiagabine Tablets)简介：
中文名：盐酸噻加宾
中文同义词： (3R)-1-[4,4-双(3-甲基噻吩-2-基)丁-3-烯基]哌啶-3-甲酸盐酸盐;盐酸噻加宾;噻加宾盐酸盐
英文名：Tiagabine Hydrochloride
别名：(3R)-1-[4,4-Bis(3-Methyl-2-Thie ... 责任编辑：admin |
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