英文药名: Topamax Sprinkle(Topiramate Capsules)

中文药名: 托吡酯胶囊

生产厂家: Janssen Pharmaceutical Inc.

适应症
本品用于初诊为癫痫的患者的单药治疗或曾经合并用药现转为单药治疗的癫痫患者。
本品用于成人及2～16岁儿童部分性癫痫发作的加用治疗。

用法用量
对成人和儿童皆推荐从低剂量开始治疗,然后逐渐增加剂量,调整至有效剂量。
片剂不要拈碎。
本品治疗成人和儿童部分性癫痫发作有效。在对照的加用治疗试验中,已证实托吡酯血浆浓度与临床疗效无相关性。尚无证据证明托吡酯在人类中有耐受性,在成人部分性癫痫发作患者中进行的剂量范围研究得出,剂量大于400mg/日(600、800和1000mg/日)并不增加疗效。
应用本品治疗时,不必监测血浆托吡酯浓度以达到最佳疗效。本品加用苯妥英治疗时,仅有极少数病例需调整苯妥英的用量以达到最佳临床疗效。在本品加用治疗期间,加用或停用苯妥英和卡马西平可能需要调整本品的剂量。
进食与否皆可服用本品。
如果您有任何疑问，请尊医嘱。
 
不良反应
依据标准WHO－ART词典对报告的不良事件进行了分类。
加用治疗临床研究。
由于托吡酯通常与其它抗癫痫药合用,因此不可能确定是哪种药物或是哪几种药物与不良事件有关。
成人
几个双盲临床试验,其中一些采用快速剂量调整,结果发现不良事件的发生率大于或等于5%,且治疗组发生率大于安慰剂组的不良事件有：嗜睡、头晕、神经质、共济失调、疲乏、言语障碍、精神运动迟缓、视觉异常、记忆困难、意识错乱、感觉异常、复视、厌食、眼球震颤、恶心、体重减轻、箫言障碍、专心/注意困难、抑郁、腹痛、无力和情绪障碍。
另外,有些不良事件虽发生率不高,但认为可能和药物有关的有：味觉倒错、激越、认知障碍、情感不稳定、协调异常、步态异常、冷漠、精神病或精神障碍、攻击反应或行为、白血球减少和肾结石。个别血栓栓塞不良事件的病例虽有报导,但其与药物的相关性尚不明确。
儿童患者
几个双盲临床试验结果发现：发生率大于或等于5%,且治疗组发生率大于安慰剂组的不良事件有：嗜睡、厌食、疲乏、神经质、损伤、人格障碍、专心/注意困难、攻击反应、体重减轻、步态异常、情绪障碍、共济失调、唾液增多、恶心、记忆障碍、多动症、头晕、言语及相关障碍和感觉异常。
另外,有些不良事件虽发生率不高,但认为可能和药物有关的有：情感不稳定、激越、冷漠、认知障碍、精神运动迟缓、意识错乱、幻觉、抑郁和白血球减少。
 
禁忌
已知对本品过敏者禁用。

注意事项
包括本品在内的抗癫痫药物应逐渐停药以使发作频率增加的可能性减至最低。在成人的临床试验中,每周减量100mg/日。某些病人在无并发症的情况下停药过程可加速。
原形托吡酯及其代谢产物的主要排泄途径为经肾脏清除。肾脏清除的能力与肾脏的功能有关,而与年龄无关。伴有中度或重度肾功能损害的患者达到稳态血浆浓度的时间可能需10－15天,而肾功能正常的患者只需4－8天。
对所有患者的剂量调整均应依据临床疗效进行(如控制发作,避免副作用),并且需了解对于已知有肾脏损害的患者,在每个剂量下达到稳态血浆浓度的时间均需延长。
服用托吡酯时应保持足够的饮水量。足够的饮水可以减少肾结石发生的风险。在运动前或运动中、或处于较高温度环境中时,保持适当的饮水量可以减少与发热有关的不良事件。
情绪障碍/抑郁
在使用本品的治疗中,曾观察到情绪障碍和抑郁的发生率有所增加。
自杀性企图
在双盲临床试验中,本品组自杀性企图的发生率为0.003(13例/3999患者),安慰剂为0(0例/1430患者)。在本品治疗双相情感障碍的临床试验中,曾有一个自杀病例的报告。
肾结石
某些患者,尤其是伴有潜在肾石病因素的患者可能有增加肾石形成以及出现有关体征和症状如肾绞痛、肾区疼痛和侧腹疼痛的危险。
肾石病的危险因素包括既往肾结石以及具有肾石病和高钙尿的家族史。但在托吡酯治疗期间,这些危险因素均未被证明可确实导致肾石形成。此外,患者服用的其它与肾石形成有关的药物可能也会增加此风险。
肝功能不全
肝功能受损的患者应慎用本品,因其对本品的清除可能下降。
营养补充
若使用本品时体重下降,可考虑补充膳食或增加进食。
对驾驶及操作机器能力的影响
与所有抗癫痫药物一样,托吡酯作用于中枢神经系统,可产生嗜睡、头晕或其它相关症状。这些不良事件虽然是轻度或中度,但均可能使患者在驾驶汽车或操纵机器时发生危险,特别是处于用药早期的患者。假性近视和继发性闭角型青光眼综合征
接受托吡酯治疗的患者中有报告出现假性近视和继发性闭角型青光眼的综合征,症状包括突发视力下降和/或眼睛痛。眼科医生的发现包括近视、前房变浅、眼充血 (发红)和眼内压升高,伴有或不伴有瞳孔扩大。这些症状可能与眼部渗出物导致晶状体和虹膜的前移,以及继发性闭角型青光眼有关。症状一般在开始托吡酯治疗的一个月内发生。与在40岁以下人群中发病率较低的原发性窄角型青光眼相比,在儿科及成人患者中均有与托吡酯有关的继发性闭角型青光眼的报告。治疗包括经治医生应立即停止给予托吡酯,并采取适当措施降低眼内压。这些措施通常会使眼内压降低。
注：任何病因引起的眼内压升高,如果不进行治疗,可能导致严重的后遗症,包括永久失明。
代谢性酸中毒
伴有高氯血症的非阴离子间隙的代谢性酸中毒(即血清重碳酸盐水平低于正常范围,又非呼吸性碱中毒)可能与使用托吡酯治疗有关。血清重碳酸盐水平的降低可能是由于托吡酯对肾脏碳酸酐酶有抑制作用。尽管重碳酸盐水平的降低可出现于治疗过程中的任何阶段,但一般出现于治疗早期,且通常为轻中度(在成人剂量为 100mg/日或以上,儿童剂量约为6mg/kg/日,平均降低4mmol/L),极个别患者重碳酸盐水平降至10mmol/L日以。易导致酸中毒的条件或治疗(如肾脏疾病、严重呼吸系统疾病、癫痫持续状态、腹泻、外科手术、酮体生成饮食或某些药物)可能会加强托吡酯降低重碳酸盐水平的作用。
儿童慢性代谢性酸中毒可影响生长发簖。尚未就托吡酯对儿童或成人生长及骨相关后遗症的作用进行系统性研究。
建议在托吡酯治疗中酌情进行包括血清重碳酸盐水平检测在内的适当评价。如有代谢性酸中毒出现并持续,应考虑降低托吡酯剂量或逐渐停药。

孕妇及哺乳期妇女用药
与其它抗癫痫药物相同,托吡酯在对小鼠、大鼠和家兔进行的试验中显示了致畸性。在对大鼠进行的试验中,托吡酯可通过胎盘屏障。未在妊娠妇女中进行本品的研究。然而,只有在潜在利益超过对胎儿可能的风险时才可在妊娠期应用本品。
托吡酯可自哺乳大鼠的乳汁中排出。在研究中未对托吡酯在人乳中的排泄进行评价,对患者有限的观察显示了托吡酯会经母乳排出。由于许多药物可经人乳排泄,哺乳期妇女用药应权衡利弊,用药期间应停止哺乳。
药物上市后曾有个例报告,妊娠妇女单用或与其它抗癫痫药合并服用时,新生男婴出现尿道下裂,但未发现该不良事件与托吡酯具有相关性。
 
药物相互作用
在本项目中,改变不超过15%即被定义为无影响。托吡酯片对其它抗癫痫药物的作用
托吡酯与其它抗癫痫药物(苯妥英、卡马西平、丙戊酸、苯巴比妥、扑痫酮)加用治疗时,除在极少数病人中发现托吡酯与苯妥英合用时可导致苯妥英血浆浓度增高外,托吡酯对其它药物的稳态血浆浓度无影响。对苯妥英的影响可能是由于对某种酶的多晶型异构体(CYP2Cmeph)的抑制作用导致的。因此,对任何服用苯妥英出现临床上的毒性症状或异常体征的患者均应监测其血浆苯妥英浓度。
一项对癫痫患者进行的药物相互作用药代动力学研究显示,使用拉莫三嗪时,加用日剂量为100 mg至400mg的托吡酯不会增加拉莫三嗪的稳态血浆浓度。停用平均日剂量为327mg的拉莫三嗪不会影响托吡酯的稳态血浆浓度。
其它抗癫痫药物对托吡酯片的影响
苯妥英和卡马西平可降低托吡酯的血浆浓度。在托吡酯治疗时加用或停用苯妥英或卡马西平时可能需要调整托吡酯的剂量。这应以临床疗效为依据来进行调整。丙戊酸的加用或停用不会产生临床上明显的托吡酯血浆浓度的改变,因此不需调整托吡酯剂量。
这些相互作用的结果综述见下表：
加用抗癫痫药物 抗癫痫药物血药浓度 托吡酯血药浓度
苯妥英 －** ↓
卡马西平(CBZ) － ↓
丙戊酸 － －
拉莫三嗪 － －
苯巴比妥 － NS
扑痫酮 － NS
－：对血浆药物浓度无影响
**：个别患者血浆药物浓度增加
↓：血浆药物浓度下降
NS：未进行研究
地高辛：一项单剂量临床研究发现因同时服用托吡酯,地高辛血清药－时曲线下面积下降12%。但此观察结果有无临床意义尚不明确。服用地高辛治疗的患者加用或停用托吡酯时都应注意监测地高辛的血清浓度。
口服避孕药：在一项与口服避孕药(1mg炔诺酮/35μg炔雌醇复方制剂)的药代动力学相互作用的研究中,只使用托吡酯一种抗癫痫药,且其剂量在 50－200mg/日时,没有引起两种避孕药成分的血浆AUC值发生统计学意义的显著变化。
在另外一项研究中发现,当托吡酯与丙戊酸合用,且托吡酯剂量为 200、400及800mg/日时,炔雌醇的血浆AUC值显著降低,降低幅度分别为18%、21%及30%。在这两项研究中(托吡酯剂量范围为 50－800mg/日),托吡酯对炔诺酮的血浆AUC值均不产生显著影响。在200－800mg/日托吡酯剂量范围内,炔雌醇血浆AUC值的降低与托吡酯给药剂量有相关性,但在50―200mg/日剂量范围内此关系却并不显著。但以上这些变化的临床意义并不显著。托吡酯与口服避孕药合用时,避孕药的疗效可能会降低,从而增加非月经性出血的可能。同时服用含雌激素成份避孕药的患者,应随时向医生报告阴道流血的任何改变特征,即使未发生阴道非正常流血,仍然存在避孕药效力降低的可能性。
氢氯噻嗪：在一项对健康志愿者进行的药物相互作用研究中,评价了单独使用及合用氢氯噻嗪(每日25mg)与托吡酯(每日2次、每次96mg)的稳态药代动力学特性。研究结果显示,在使用托吡酯时加入氢氯噻嗪,会使托吡酯的Cmax升高27%,AUC增加29%。尚不知此变化的临床意义。因此,在使用托吡酯时加入氢氯噻嗪,可能需要调整托吡酯的用药剂量。与托吡酯合用对氢氯噻嗪稳态药代动力学无显著影响。临床检验结果显示,单独使用托吡酯或氢氯噻嗪后,血钾浓度有所降低,其降低程度大于两药物合用造成的血钾降低程度。
中枢神经抑制剂：未进行过本品与乙醇或其它中枢神经抑制剂同服的临床研究,但是建议本品不要与乙醇或其它中枢神经抑制剂同服。
二甲双胍：一项在健康志愿者体内进行的药物相互作用研究显示了单独使用二甲双胍和二甲双胍与托吡酯合用时的两种药物血浆中的稳态药代动力学。研究结果显示,在与托吡酯合用时,二甲双胍Cmax和AUC0-12h的平均值分别增加了18%和25%,而CL/F平均值下降了20%,但托吡酯并不影响二甲双胍的tmax。托吡酯对二甲双胍药动学的影响在临床上的意义尚不明确。与二甲双胍合用时,托吡酯的口服血浆清除率有所降低,尚不知改变的程度。二甲双胍对托吡酯药动学的影响在临床上的意义尚不明确。在接受二甲双胍治疗的患者,若增加或停止托吡酯的治疗,应密切注意常规监测以有效地控制其糖尿病病情。
匹格列酮：在一项对健康志愿者进行的药物相互作用研究中,评价了单独使用及合用匹格列酮与托吡酯的稳态药代动力学特性。匹格列酮的AUC降低15%,而 Cmax未受影响。此发现不具有统计学意义。可注意到,活性羟基代谢产物的Cmax和AUC分别下降13%和16%,活性酮基代谢产物的Cmax和AUC 均下降60%。尚不知这些现象的临床意义。当本品与匹格列酮合用时,应注意对患者糖尿病病情的适当控制。其它药物：与其它易引起肾结石的药物同时使用时,可能会增加肾结石的风险。因此,在使用托吡酯片时,应避免使用这类药物,因为这些药物可能产生一种增加肾结石形成风险的生理环境。
实验室检验：临床试验数据显示,使用托吡酯时血清碳酸氢盐水平会平均减少4mmol/L。
药物过量

体征和症状
曾有本品药物过量的报告,症状和体征包括惊厥、困倦、言语障碍、视力模糊、复视、精神损害、嗜睡、共济失调、木僵、低血压、腹痛、激越、眩晕和抑郁。多数病例的临床后果并不严重,但有多种药物(包括本品)过量后死亡的报告。
本品过量可能导致严重的代谢性酸中毒。
一名服用了96－110克托吡酯的患者因昏迷20－24小时被送入医院,3－4天后完全恢复。
治疗
本品急性中毒时,如刚刚摄入,应立即通过洗胃或催吐清除胃内尚未吸收的药物。体外试验显示活性炭可以吸收本品,还可以采取适当的支持性治疗。血液透析是清除体内托吡酯的一种有效方法。患者应大量补水。
贮藏
避光,干燥,室温密闭保存。

剂型与规格：
胶囊剂：15mg  25mg  50mg

Topamax Sprinkle CapsulesGeneric Name: Topiramate (toe-PIR-a-mate)Brand Name: Topamax
Topamax Sprinkle Capsules are used for:
Treating seizures in certain patients. It may be used alone or with other medicines. It is also used to prevent migraine headaches. It may also be used for other conditions as determined by your doctor.

Topamax Sprinkle Capsules are an anticonvulsant that is also effective for preventing migraine headaches. It affects several chemicals in the brain that help to reduce seizure activity and prevent migraine headaches from occurring.

Do NOT use Topamax Sprinkle Capsules if:
you are allergic to any ingredient in Topamax Sprinkle Capsules
you are taking a carbonic anhydrase inhibitor (eg, acetazolamide)
Contact your doctor or health care provider right away if any of these apply to you.

Before using Topamax Sprinkle Capsules:
Some medical conditions may interact with Topamax Sprinkle Capsules. Tell your health care provider if you have any medical conditions, especially if any of the following apply to you:

if you are pregnant, planning to become pregnant, or are breast-feeding
if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
if you have allergies to medicines, foods, or other substances
if you have liver or kidney problems, kidney stones, osteoporosis (weak bones), or metabolic problems, you drink alcohol regularly, or you are on a ketogenic diet
if you have diarrhea, lung or breathing problems, or low bicarbonate levels in the blood, or you will be having surgery
if you have a history of status epilepticus (continuous seizure activity or a series of seizures without a full return to consciousness)
if you have a history of mental or mood problems, or suicidal thoughts or actions
Some MEDICINES MAY INTERACT with Topamax Sprinkle Capsules. Tell your health care provider if you are taking any other medicines, especially any of the following:

Anticholinergics (eg, benztropine), carbonic anhydrase inhibitors (eg, acetazolamide), haloperidol, or tricyclic antidepressants (eg, nortriptyline) because the risk of decreased sweating may be increased
Valproic acid because a serious side effect with symptoms of confusion, lethargy, and vomiting may occur
Metformin or pioglitazone because blood glucose control may be altered; monitor your blood sugar carefully if you use Topamax Sprinkle Capsules with metformin or pioglitazone
Hydrochlorothiazide because it may increase the risk of Topamax Sprinkle Capsules's side effects
Carbamazepine or hydantoins (eg, phenytoin) because they may decrease Topamax Sprinkle Capsules's effectiveness
Amitriptyline because the risk of its side effects may be increased by Topamax Sprinkle Capsules
Lithium because Topamax Sprinkle Capsules may have an effect on lithium blood levels
Hormonal birth control (eg, birth control pills) or risperidone because their effectiveness may be decreased by Topamax Sprinkle Capsules
This may not be a complete list of all interactions that may occur. Ask your health care provider if Topamax Sprinkle Capsules may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Topamax Sprinkle Capsules:
Use Topamax Sprinkle Capsules as directed by your doctor. Check the label on the medicine for exact dosing instructions.

An extra patient leaflet is available with Topamax Sprinkle Capsules. Talk to your pharmacist if you have questions about this information.
Take Topamax Sprinkle Capsules by mouth with or without food.
Drink plenty of fluids while taking Topamax Sprinkle Capsules to prevent kidney stones from forming.
The capsules may be swallowed whole. You may also open the capsules and sprinkle the contents over a spoonful of soft food, such as applesauce, custard, ice cream, oatmeal, pudding, or yogurt. Do not crush or chew the beads inside the capsule.
To open the capsules, hold the capsule upright so that you can read the word "top." Carefully twist off the clear portion of the capsule. It is best to do this over the small portion of soft food. Sprinkle all of the capsule's contents onto the spoonful of soft food.
Swallow this mixture immediately; do not chew it. Drink fluid immediately after taking the medicine to be sure all of the mixture is swallowed. Do not save the mixture for use at a later time.
Do not suddenly stop taking Topamax Sprinkle Capsules. Suddenly stopping Topamax Sprinkle Capsules may cause seizures to occur more often. If you need to stop Topamax Sprinkle Capsules, your doctor will gradually lower your dose.
If you miss a dose of Topamax Sprinkle Capsules, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.
Ask your health care provider any questions you may have about how to use Topamax Sprinkle Capsules.

Important safety information:
Topamax Sprinkle Capsules may cause drowsiness, dizziness, confusion, or trouble concentrating. These effects may be worse if you take it with alcohol or certain medicines. Use Topamax Sprinkle Capsules with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.
Do not drink alcohol or use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Topamax Sprinkle Capsules; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.
Topamax Sprinkle Capsules may reduce sweating, which could raise body temperature, especially in children. This risk is greater in hot weather and/or during vigorous exercise. Drink plenty of fluids. Dress lightly while in hot climates or when exercising. Check carefully for signs of decreased sweating. If this occurs, promptly seek cooler or air-conditioned shelter and/or stop exercising. Seek medical attention right away if you have unexplained fever, or if you have mental or mood changes, headache, or dizziness.
Tell your doctor or dentist that you take Topamax Sprinkle Capsules before you receive any medical or dental care, emergency care, or surgery.
Hormonal birth control (eg, birth control pills) may not work as well while you are using Topamax Sprinkle Capsules. To prevent pregnancy, use an extra form of birth control (eg, condoms).
Lab tests, including serum bicarbonate levels, may be performed while you use Topamax Sprinkle Capsules. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.
Use Topamax Sprinkle Capsules with caution in the ELDERLY; they may be more sensitive to its effects.
Caution is advised when using Topamax Sprinkle Capsules in CHILDREN; they may be more sensitive to its effects, especially decreased sweating and decreased bicarbonate levels.
Topamax Sprinkle Capsules may affect growth rate in CHILDREN and teenagers in some cases. They may need regular growth checks while they take Topamax Sprinkle Capsules.
Topamax Sprinkle Capsules should be used with extreme caution in CHILDREN for migraines and in CHILDREN younger than 2 years old for seizures; safety and effectiveness in these children have not been confirmed.
PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Topamax Sprinkle Capsules while you are pregnant. Topamax Sprinkle Capsules are found in breast milk. If you are or will be breast-feeding while you use Topamax Sprinkle Capsules, check with your doctor. Discuss any possible risks to your baby.
Possible side effects of Topamax Sprinkle Capsules:
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; decreased sweating; diarrhea; dizziness; drowsiness; dry mouth; flu-like symptoms; headache; loss of appetite; nausea; nervousness or anxiety; numbness or tingling of the skin; runny nose; sore throat; stomach pain or upset; taste changes; tiredness; trouble sleeping; weight loss.

Seek medical attention right away if any of these SEVERE side effects occur:
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blood in the urine; blurred vision; bone pain; chest pain; confusion; decreased coordination; depression; double vision or other vision changes; eye pain; irregular heartbeat; loss of consciousness; memory problems; menstrual changes; mental or mood changes; muscle or joint pain, cramps, or weakness; rapid, shallow breathing; red, swollen, blistered, or peeling skin; ringing in the ears; severe or persistent loss of appetite; severe stomach, side, or back pain; significant weight loss; speech problems; stupor; suicidal thoughts or actions; tremor; trouble thinking, concentrating, or remembering things; trouble walking; unexplained fever; unusual bruising or bleeding; unusual eye movements; unusual tiredness.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects at .

If OVERDOSE is suspected:
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center or emergency room immediately. Symptoms may include agitation; depression; lethargy; loss of coordination; mental impairment; seizures; severe drowsiness or dizziness; severe or persistent stomach pain; stupor; vision problems (eg, blurred or double vision).

Proper storage of Topamax Sprinkle Capsules:
Store Topamax Sprinkle Capsules at room temperature, below 77 degrees F (25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Topamax Sprinkle Capsules out of the reach of children and away from pets.

General information:
If you have any questions about Topamax Sprinkle Capsules, please talk with your doctor, pharmacist, or other health care provider.
Topamax Sprinkle Capsules are to be used only by the patient for whom it is prescribed. Do not share it with other people.
If your symptoms do not improve or if they become worse, check with your doctor.
This information is a summary only. It does not contain all information about Topamax Sprinkle Capsules. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.