英文药名: Aloxi(Palonosetron)

中文药名: 盐酸帕洛诺司琼注射剂

英文商品名: PALONOSETRON(ALOXI GENERIC)

英文药品名: PALONOSETRON HCL

英文化合物名称: (3aS)-2-(3S)-1-Azabicyclo[2.2.2]oct-3-yl-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one monohydrochloride

中文商品名: 帕洛诺司琼(ALOXI仿制药)

中文化合物名称:（3aS）-2-(S)-1-氮杂双环［2,2,2］辛-3-基］-2,3,3a,4,5,6-六氢化-1-氧-1-苯[反]异喹啉盐酸盐

规格：PALONOSETRON(ALOXI GENERIC) 0.25MG/5ML/VIAL

药品说明

癌症化疗几乎都会出现不同程度的恶心和呕吐，如顺铂治疗的发生率就超过99％。化疗引起的恶心和呕吐（CINV）占据了病人畏惧化疗的前三种因素之一。在所有药物治疗手段中，皮质类固醇和5－HT3受体拮抗剂应用最广泛。现有 5－HT3受体拮抗剂（如昂丹司琼，格拉司琼，多拉司琼）在抗呕吐、有效性和耐受性方面认为是类似的。它们对于CINV急性期有效，但延迟期效果不佳，对于后一种情况，往往单用皮质类固醇或合用其他制剂。

帕洛诺司琼是由Helsinn Healthcare公司研制的选择性5-羟色胺3受体拮抗剂(5-HT3)。盐酸帕洛诺司琼(Palonosetron)注射剂以商品名Aloxi于2003年7月由美国FDA批准，用于预防在实施中度或重度致呕吐性化疗方案时所引起的急性和迟发性呕吐。

帕洛诺司琼对5-HT3受体有高选择性拮抗作用，可阻断呕吐反射中枢外周神经厚的突触前5HT3受体的兴奋，并且直接影响中枢神经系统内5HT3受体转递的迷走神经传入后区的作用，阻断肠道中迷走神经末梢，阻止信号传递到5-HT3受体触发区，减少呕吐和恶心的发生率。

化学成分
帕洛诺司琼盐酸盐是一种介于白色及掺有少量灰黄色的白色之间的晶状粉末。易溶于水，也能溶于丙二醇，微溶于乙醇和2-丙醇。Aloxi注射液是一种无菌，清澈，无色，非高温合成，等渗的用于静脉的药物。每5ml的Aloxi注射瓶内含有0.25mg帕洛诺司琼。注射液的pH值在4.5～5.5之间。

化学名：（3aS）-2-(S)-1-氮杂双环［2,2,2］辛-3-基］-2,3,3a,4,5,6-六氢化-1-氧-1-苯[反]异喹啉盐酸盐;(3aS)-2-(3S)-1-Azabicyclo[2.2.2]oct-3-yl-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one monohydrochloride

分子式： C19H24N2O.HCl

药效学特征

帕洛诺司琼是一个高选择性，竞争性二代5－HT3受体高亲和性药物。在放射配体结合试验中，使用NG108-15细胞中［3H］-quizapine作为放射配体，帕洛诺司琼替换结合NG-108-15细胞的5HT3受体,抑制常数的负对数（Pki）为10.4，28个其他受体包括其他5－羟色胺亚型的亲和力都较低（Pki<6.0）。帕洛诺司琼5－HT3受体亲和性（Pki>10）高于其他5－HT3受体拮抗剂100倍（格拉司琼为8.91，曲匹司琼为8.81，昂丹司琼为8.39，多拉司琼是7.6）。胃肠外应用帕洛诺司琼可剂量依赖性的抑制2－甲基－5－羟色胺诱导的与大鼠 bezold-Jarisch反射有关的心动过缓。帕洛诺司琼在抑制bezold-Jarisch反射方面比格拉司琼效力强15倍，比昂丹司琼强55倍，并且作用时间长。口服或静注帕洛诺司琼可剂量依赖性的抑制动物模型中，顺铂、达卡巴嗪、放线菌素或氮芥引起的呕吐，效力强于昂丹司琼或格拉司琼2～93倍。在狗口服剂量范围1～100μｇ/ｋｇ内，4个灭吐灵催吐的试验中有3个实现完全抑制呕吐反应，全抑制所需剂量至少比昂丹司琼低10倍。而且，对于顺铂引起的呕吐，帕洛诺司琼（30μｇ/ｋｇ口服）作用持续时间为7h，同样有效剂量（300μｇ/ｋｇ口服）的昂丹司琼为4h。类似于昂丹司琼,帕洛诺司琼对于阿扑吗啡引起的呕吐无效果。麻醉狗静注帕洛诺司琼剂量达到1mg/kg对于血流动力学或ECG参数无明显改变。

药代动力学特征

癌症病人的静注帕洛诺司琼的参数与健康受试者类似。

吸收和分布

帕洛诺司琼在健康受试者和癌症患者的药代动力学在1～90μｇ/ｋｇ范围内为线性，与剂量呈比例。对于癌症病人接受此范围内的单剂量静注帕洛诺司琼，平均最大血浆浓度（Cmax）为0.89～336ng/ml，AUC∞为13.8～957（ng・h）/ml。6个癌症病人在静注帕洛诺司琼3μｇ/ｋｇ（相当于70公斤体重的成人固定剂量0.25mg）后的平均Cmax和 AUC∞值为5.6ng/ml和35.8（ng・h）/ml。

帕洛诺司琼与血浆蛋白中等结合（62％）。10μｇ/ｋｇ单剂量静注后的分布体积约为8.3L/ｋｇ。

代谢和排泄

约50％静注剂量的帕洛诺司琼在肝中通过多种途径代谢。两种主要的代谢产物N-氧化－帕洛诺司琼和6－（S）－羟基－帕洛诺司琼是无活性的5－HT3受体拮抗剂（<帕洛诺司琼活性的1％）；体外试验中，帕洛诺司琼主要通过细胞色素P450（CYP）2D6酶，少数通过CYP3A和CYP1A2代谢。在应用单剂量帕洛诺司琼10μｇ/ｋｇ的144h之内，约80％的药物在尿中排除，其中半数为原型药（剂量的40％），代谢产物约占50％。帕洛诺司琼健康受试者的总体和肾清除率为160和66.5（ml・h）kg。帕洛诺司琼的慢清除速度导致了半衰期长达40h。由于半衰期长，在给药7日内无需再给药。明显长于其他药物（昂丹司琼4h；曲匹司琼7.3h；多拉司琼7.5h；格拉司琼8.9h）。

临床研究

帕洛诺司琼的剂量（0.25mg和0.75mg）是基于随机，双盲，剂量变化的试验结果。2个双盲试验（n=563和569）比较了帕洛诺司琼（0.25mg和0.75mg）与昂丹司琼32mg或多拉司琼100mg在抑制中度致吐剂包括氨甲喋呤>250mg/m2，环磷酰胺＜1500mg/m2，阿霉素>25mg/m2，顺铂≤50mg/m2或任意剂量的卡铂造成的CINV。受试者使用帕洛诺司琼0.25mg或0.75mg在中度化疗后的急性期（0～24h）通常得到较高的全反应率；帕洛诺司琼0.25mg急性期的全反应率显著高于昂丹司琼32mg组，类似于多拉司琼100mg。帕洛诺司琼0.75mg组的全反应率类似于昂丹司琼32mg或多拉司琼100mg组；帕洛诺司琼抗中度化疗引起的恶心/呕吐的作用在延迟期（24～120h）也能保持（次要终点指标）。帕洛诺司琼0.25mg优于昂丹司琼32mg或多拉司琼100mg,差异有显著性。帕洛诺司琼0.75mg的全反应率类似于昂丹司琼32mg，明显高于多拉司琼100mg；在总体时间内（0～120h），帕洛诺司琼0.25mg的全反应率显著高于昂丹司琼32mg（69%比50％；P＜0.001）或多拉司琼100mg（46%比34％；P＝0.021）；帕洛诺司琼0.75mg组的全反应率对比多拉司琼为59％比47％（P＝0.012）。

总之,次要终点指标也显示帕洛诺司琼至少与昂丹司琼或多拉司琼效果一样。例如，虽然急性期全控制率无组间差别，但延迟期和总体时间内，帕洛诺司琼0.25mg或0.75mg比例（42%～67％）显著高于（所有的P≤0.03）对照（31%～50％）。急性，延迟和总体时间内，帕洛诺司琼0.25mg组的呕吐发生率明显少于昂丹司琼32mg（全部P≤0.05）或多拉司琼100mg（全部P<0.02）。在延迟期和总体时间内，帕洛诺司琼0.75mg组比多拉司琼100mg更有效（P<0.002）。

单剂量帕洛诺司琼（0.25mg或0.75mg）抗呕吐作用持续时间超过120h。Kaplan-Meier分析显示帕洛诺司琼0.25mg治疗失败的出现时间明显长于昂丹司琼32mg（P＝0.0003）或多拉司琼100mg（P<0.002）。

另外，对于重度化疗，包括顺铂≥60mg/m2，或环磷酰胺>1500mg/m2来说，帕洛诺司琼也有抑制重度化疗引起的CINV作用。

耐受性

帕洛诺司琼单剂静注应用于化疗前，中度或重度化疗病人通常耐受性好。由于癌症病人并发症多，副反应发生率高，因此确定它们的诱因较困难。但多数副反应（84％）强度轻微，且/或与帕洛诺司琼治疗无关（>80％）。严重副反应发生率低（≤5％），帕洛诺司琼组和对照组类似。所有严重副反应评价为与试验无关。总结了治疗中病人出现的副反应，从高到低依次为头痛、便秘、腹泻、眩晕、乏力、腹痛、失眠。

总之，帕洛诺司琼的副反应在类型、频率、持续时间和强度上都类似于对照组。在研究者确认的至少可能与治疗有关的副反应中，头痛和便秘是最常见的。

讨论

在北美和（或）欧洲有4个选择性5－HT3受体拮抗剂用于抑制急性化疗引起的恶心和呕吐（CINV）：多拉司琼、昂丹司琼、格拉司琼和曲匹司琼。虽然这些药物在5－HT3受体亲和性，选择性和代谢方面有一定差异，但这些差异还没有导致临床上有效性的不同。因此，根据目前研究，这些5－HT3受体拮抗剂在效果上是一致的，在同样剂量下可以互换使用，这点已是共识。

所有一代5－HT3受体拮抗剂显示对于急性CINV的有效性，单剂的急性反应率从50％～70％。对于延迟性CINV的效果没有充分显示，有一部分病人在中度或重度化疗后仍有恶心和呕吐。因此，有必要开发新型更有效抑制CINV的药物。

帕洛诺司琼是首个，且目前已批准唯一的可用于开始化疗和多疗程化疗的延迟性CINV的5-HT3受体拮抗剂。它也用于抑制中度或重度致吐剂引起的急性CINV。帕洛诺司琼近来已收录于国家综合性癌症网络系统抗呕吐指南中（美国综合癌症网络（NCCN）的临床指南广泛应用于癌症治疗领域，在业界享有很高声誉）。近日NCCN推举Aloxi（palonosetron，帕洛诺司琼）注射液作为首选药物，预防中度致吐性化疗（3、4级）引起的恶心、呕吐。同时，NCCN推荐Aloxi注射液每日1次给药，预防高度致吐性化疗（5级）引起的恶心、呕吐。在临床试验中，帕洛诺司琼0.25mg或0.75mg在抑制中度或重度化疗引起的CINV，和对照药类似或更有效，耐受性较好。

Aloxi (R)(帕洛诺司琼)自问世后，2004年全年销售额为1.593亿美元。经过18个月的推广，注射剂帕洛诺司琼已成为同类品种的领先者，是一个有相当发展前景的癌症化疗抗吐药物。

Generic Name: Palonosetron

Brand Name: Aloxi

Palonosetron is used for:

Preventing nausea and vomiting caused by cancer chemotherapy. It is also used to prevent nausea and vomiting after surgery. It may also be used for other conditions as determined by your doctor.

Palonosetron is 5-HT3 receptor blocker. It works by blocking the action of serotonin in certain parts of the brain and nervous system, which helps reduce or prevent nausea and vomiting.

Do NOT use Palonosetron if:

you are allergic to any ingredient in Palonosetron

you are taking apomorphine

Contact your doctor or health care provider right away if any of these apply to you.

Before using Palonosetron:

Some medical conditions may interact with Palonosetron. Tell your doctor or pharmacist 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 are allergic to other 5-HT3 receptor antagonists (eg, ondansetron)

if you have a history of heart problems (eg, irregular heartbeat, prolonged QT), an abnormal heart function test (eg, electrocardiogram [ECG]), or low blood levels of potassium or magnesium

Some MEDICINES MAY INTERACT with Palonosetron. Tell your health care provider if you are taking any other medicines, especially any of the following:

Apomorphine because side effects such as severely low blood pressure or loss of consciousness may occur

This may not be a complete list of all interactions that may occur. Ask your health care provider if Palonosetron 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 Palonosetron:

Use Palonosetron as directed by your doctor. Check the label on the medicine for exact dosing instructions.

An extra patient leaflet is available with Palonosetron. Talk to your pharmacist if you have questions about this information.

Palonosetron is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Palonosetron at home, a health care provider will teach you how to use it. Be sure you understand how to use Palonosetron. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.

Do not use Palonosetron if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.

Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.

If you miss a dose of Palonosetron, contact your doctor right away.

Ask your health care provider any questions you may have about how to use Palonosetron.

Important safety information:

Palonosetron may cause drowsiness or dizziness. These effects may be worse if you take it with alcohol or certain medicines. Use Palonosetron with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.

Palonosetron should be used with extreme caution in CHILDREN younger than 18 years old; 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 Palonosetron while you are pregnant. It is not known if Palonosetron is found in breast milk. Do not breast-feed while you are using Palonosetron.

Possible side effects of Palonosetron:

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; headache; pain, swelling, or redness at the injection site; tiredness.

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); chest pain; fainting; fast, slow, or irregular heartbeat; fever, chills, or sore throat; trouble urinating; unusual muscle movement.
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. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Palonosetron side effects (in more detail)

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.

Proper storage of Palonosetron:

Palonosetron is usually handled and stored by a health care provider. If you are using Palonosetron at home, store Palonosetron as directed by your pharmacist or health care provider. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Palonosetron out of the reach of children and away from pets.

General information:

If you have any questions about Palonosetron, please talk with your doctor, pharmacist, or other health care provider.

Palonosetron is 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.

Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Palonosetron. 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.