——美FDA批准奥氮平肌肉内注射用缓释悬浮液Zyprexa Relprevv治疗精神分裂症
日前,美国FDA批准了Eli Lilly公司开发的奥氮平(olanzapine)注射用缓释悬浮液Zyprexa Relprevv,用于每2～4wk肌肉内注射1次治疗成人精神分裂症。FDA是主要依据一项对2045例精神分裂症患者进行的广泛临床试验数据作出上述Zyprexa Relprevv批准决定的。

部分中文Zyprexa处方资料（仅供参考）
药品名称
英文名：Olanzapine(Zyprexa)
正式名: 奥氮平[Olanzapine]
商品名: 再普乐[ZYPREXA]
药理作用
奥氮平是一种抗精神病药，对多种受体系统具有药理作用。动物试验表明，奥氮平对5-HT、多巴胺D、α-肾上腺素、组胺H等多种受体有亲和力。动物行为研究表明，奥氮平具有5-HT、多巴胺和胆碱能拮抗作用，与其受体结合情况相符。奥氮平的体外和体内5-HT2受体亲和力大于其与多巴胺D2受体的亲和力。电生理研究表明，奥氮平选择性地减少间脑边缘系统（A10）多巴胺能神经元的放电，而对纹状体（A9）的运动功能通路影响很小。奥氮平在低于产生僵住反应的剂量水平时能减少条件性回避反应。与其它抗精神病药不同，奥氮平在抗焦虑测试中能增加反应。对照临床试验结果表明，奥氮平能显著改善阴性及阳性症状。

适应症
奥氮平用于治疗精神分裂症。
初始治疗有效的患者，奥氮平在维持治疗期间能够保持其临床效果。
奥氮平用于治疗中、重度躁狂发作。
对奥氮平治疗有效的躁狂发作患者，奥氮平可用于预防双相情感障碍的复发。
用法用量
精神分裂症：
奥氮平的建议起始剂量为10mg/天，每日一次，与进食无关。
在精神分裂症的治疗过程中，可以根据患者的临床状态调整日剂量为5－20mg/天。建议经过适当的临床评估后，剂量可增加至10mg/天的常规剂量以上，加药间隔不少于24小时。停用奥氮平时应逐渐减少剂量。

躁狂发作：
单独用药时起始剂量为每日15mg，合并治疗时每日10mg。
预防双相情感障碍复发：
推荐起始剂量为10mg/日。对于使用奥氮平治疗躁狂发作的患者，预防复发的持续剂量同前。对于新发躁狂、混合发作或抑郁发作，应继续奥氮平治疗（需要时剂量适当调整），同时根据临床情况合并辅助药物治疗情感症状。

在精神分裂症、躁狂发作和双相情感障碍的预防治疗过程中，可根据个体临床状况不同，在5－20mg/日的范围内相应调整每日剂量。建议仅在适当的临床再评估后方可使用超过推荐剂量的药物，且加药间隔不少于24小时。停用奥氮平时应逐渐减少剂量。
任何疑问，请遵医嘱！
禁忌症
本品禁用于已知对奥氮平过敏的患者。
本品慎用于有下列情况的患者：
1.有癫痫史或有癫痫相关疾病者；
2.任何原因所致的白细胞和/或中性粒细胞降低者；
3.有药物所致骨髓抑制/毒性反应史者；
4.伴发疾病、放疗或化疗所致的骨髓抑制；
5.嗜酸性粒细胞过多性疾病或骨髓及外骨髓增生性疾病；
6.前列腺增生、麻痹性肠梗阻和窄角性青光眼患者。
不良反应
临床试验中与奥氮平使用有关的主要不良反应是嗜睡和体重增加。在有痴呆的老年患者中，与奥氮平治疗有关的死亡率和脑血管不良事件比安慰剂高。少数患者在治疗中出现血糖和甘油三脂水平升高。奥氮平对血浆催乳素浓度影响甚微，因而无男性乳房增大、泌乳和女性月经紊乱、闭经等临床表现。偶见不良反应包括头晕，静坐不能，口干，便秘，外周水肿，直立性低血压及肝转氨酶－过性升高。

注意事项
奥氮平可引起嗜睡，从事危险作业时应谨慎。若和酒精同服，可使奥氮平的镇静作用增强。患者长期服用抗精神病药（包括奥氮平），如果出现迟发性运动障碍的体征或症状，应减药或停药。若出现神经阻滞剂恶性综合症（NMS）的临床表现（如：高热肌强直精神状态改变及植物神经紊乱等），应立即停用所有抗精神病药，包括奥氮平。

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【原产地英文商品名】ZYPREXA RELPREVV
【原产地英文药品名】OLANZAPINE PAMOATE
【中文参考商品译名】
注：以下产品不同规格和不同价格，购买时请以电话咨询为准！
·再普乐 RELPREVV 405毫克/瓶
·再普乐 RELPREVV 300毫克/瓶
·再普乐 RELPREVV 210毫克/瓶
【中文参考药品译名】奥氮平PAMOATE
【生产厂家中文参考译名】礼来
【生产厂家英文名】LILLY

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ZYPREXA RELPREVV
Marketed by:
Eli Lilly and Co (Indianapolis, IN)
Indication:
The FDA recently approved ZYPREXA RELPREVV (olanzapine) for Extended-Release Injectable Suspension for the treatment of schizophrenia in adults. The product is a long-acting intramuscular injection that sustains the delivery of olanzapine for up to 4 weeks. ZYPREXA RELPREVV is intended for deep intramuscular gluteal injection only. Dosages may include the following: 150 mg/2 weeks, 210 mg/2 weeks, 300 mg/2 weeks, 300 mg/4 weeks, or 405 mg/4 weeks. Note that 2 ZYPREXA RELPREVV intramuscular formulations exist with different dosing schedules. ZYPREXA IntraMuscular (10 mg/vial) is a short-acting formulation and should not be confused with ZYPREXA RELPREVV.

Dosage Form:
Powder for suspension for intramuscular use only: 210 mg/vial, 300 mg/vial, and 405 mg/vial
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FDA Approves Lilly's ZYPREXA® RELPREVV™ for Treatment of Schizophrenia in Adults
Long-acting injection provides therapeutic olanzapine exposure for up to four weeks
INDIANAPOLIS - December 17, 2009 /PRNewswire/ — The U.S. Food and Drug Administration (FDA) approved ZYPREXA RELPREVV (olanzapine) For Extended Release Injectable Suspension for the treatment of schizophrenia in adults, Eli Lilly and Company (NYSE: LLY) announced today. ZYPREXA RELPREVV, a long-acting intramuscular injection, sustains the delivery of olanzapine for up to four weeks.

Different from both oral and injected short-acting formulations, long-acting formulations of antipsychotics allow for stable concentrations of the active drug to remain at a therapeutic range for an extended period of time.i

"Patients, families and communities often needlessly suffer the consequences of relapse when daily schizophrenia medications are not taken as prescribed," said John Kane, M.D., chairman, Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, N.Y. "ZYPREXA RELPREVV gives patients an additional treatment option that can help them maintain therapeutic drug levels for up to four weeks at a time."

Approximately 2.4 million Americans or about 1.1 percent of the adult population have schizophrenia.ii Schizophrenia is a brain disorder characterized by acute episodes of delusions (false beliefs that cannot be corrected by reason) and hallucinations (usually in the form of non-existent voices), as well as long-term impairments such as diminished emotion, general lack of interest and depressive signs and symptoms.iii, iv

Proper treatment for schizophrenia can relieve symptoms, prevent or delay relapse and break the "revolving door" cycle often associated with schizophrenia.v, vi Non-adherence to antipsychotic medications greatly increases the risk of relapse in patients with schizophrenia.vii By administering long-acting medications, psychiatrists know when patients have received their medication and can immediately detect non-adherence when a patient does not return for a scheduled injection.viii

"There is a growing recognition among psychiatrists in the United States that non-adherence to medication is an even greater barrier to care for patients with schizophrenia than was previously understood, and that long-acting treatments can play a beneficial role in helping patients maintain a stable treatment regimen," said John Hayes, M.D., vice president of Lilly Research Laboratories. "ZYPREXA RELPREVV provides a new mechanism for helping appropriate patients benefit from the well-characterized efficacy of olanzapine."

The FDA approval is based on a broad clinical data package involving 2,054 patients, in which ZYPREXA RELPREVV was found to be effective in controlling symptoms of schizophrenia, including hallucinations, delusions, apathy and social withdrawal. Efficacy was shown without the need for oral supplementation. Clinical data showed that ZYPREXA RELPREVV dosages (150, 210, 300 and 405 mg) provide therapeutic olanzapine exposure for two or four weeks depending on the dose.

ZYPREXA RELPREVV was found to have a similar safety profile as oral olanzapine, with the exception of injection-related events, including post-injection delirium/sedation syndrome (PDSS). PDSS events include a wide range of signs and symptoms of sedation, from mild in severity to coma, and/or delirium, including confusion, disorientation, agitation, anxiety or other cognitive impairment. As of November 30, 2009, across all clinical trials, PDSS events have occurred in < 0.1 percent of injections and approximately 2 percent of patients. The potential for onset of an event is greatest with-in the first hour after injection. The majority of cases have occurred within the first three hours after injection; however cases have occurred after three hours. All patients largely recovered within 72 hours, and the majority of these patients have chosen to continue treatment with ZYPREXA RELPREVV. Labeling for ZYPREXA RELPREVV includes a requirement for the patient to be observed at a healthcare facility with ready access to emergency response services for at least three hours following each injection and to be accompanied to his or her destination upon leaving the facility.
Lilly worked with the FDA to develop a Risk Evaluation and Mitigation Strategy (REMS), which includes a communication plan, a patient medication guide and a mandatory Patient Care Program, which restricts distribution of ZYPREXA RELPREVV to prescribers, healthcare facilities, pharmacy service providers and patients enrolled in the program. The goal of the Patient Care Program is to mitigate the risk of negative outcomes associated with ZYPREXA RELPREVV PDSS.
This treatment has been approved in the European Union under the trade name Zypadhera™ and in New Zealand and Australia under the trade name ZYPREXA RELPREVV.
Safety Information for ZYPREXA RELPREVV (olanzapine) For Extended Release Injectable Suspension
ZYPREXA RELPREVV is indicated in the United States for the treatment of schizophrenia in adults.
Zyprexa oral is indicated in adults in the United States for the treatment of schizophrenia, acute treatment of mixed and manic episodes of bipolar I disorder, and maintenance treatment of bipolar I disorder.
Adverse events with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, have been reported following injections of ZYPREXA RELPREVV. ZYPREXA RELPREVV must be administered in a registered healthcare facility with ready access to emergency response services. After each injection, patients must be observed at the healthcare facility by a healthcare professional for at least three hours. Because of this risk, ZYPREXA RELPREVV is available only through a restricted distribution program called ZYPREXA RELPREVV Patient Care Program and requires prescriber, healthcare facility, patient, and pharmacy enrollment.
Olanzapine is not approved for the treatment of patients with dementia-related psychosis. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
In addition, compared to elderly patients with dementia-related psychosis taking a placebo, there was a significantly higher incidence of cerebrovascular adverse events (e.g., transient ischemic attack) in elderly patients with dementia-related psychosis treated with olanzapine.
As with all antipsychotic medications, a rare and potentially fatal condition known as Neuroleptic Malignant Syndrome (NMS) has been reported with olanzapine. If signs and symptoms appear, immediate discontinuation is recommended. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
Hyperglycemia, in some cases associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics, including olanzapine. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics. Physicians should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level. Patients taking olanzapine should be monitored regularly for worsening of glucose control. Patients starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose testing.
Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and follow-up lipid evaluations in patients using olanzapine, is advised. Clinically significant, and sometimes very high, elevations in triglyceride levels and modest mean elevations in total cholesterol have been observed with olanzapine use.
Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring of weight.
Also, as with all antipsychotic treatment, prescribing should be consistent with the need to minimize Tardive Dyskinesia (TD). The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic increase. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia, and in some patients, syncope, especially during the initial dose-titration period. Particular caution should be used in patients with known cardiovascular disease,cerebrovascular diseases, or those predisposed to hypotension.
The possibility of a suicide attempt is inherent in schizophrenia. Close supervision of high-risk patient should accompany drug therapy.
Other potentially serious adverse events include decreased white blood cell count (leukopenia, neutropenia, agranulocytosis), seizures, elevated prolactin levels, cognitive and motor impairment, body temperature elevation, and trouble swallowing.
The most common treatment-emergent adverse events (≥5% in at least one of the ZYPREXA RELPREVV treatment groups and greater than placebo) in the short-term, placebo-controlled trial were headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting.
The most common treatment-emergent adverse event associated with oral Zyprexa in placebo-controlled, short-term schizophrenia and bipolar mania trials was somnolence. Other common events were dizziness, weight gain, personality disorder (COSTART term for nonaggressive objectionable behavior), constipation, akathisia, postural hypotension, dry mouth, asthenia, dyspepsia, increased appetite and tremor.

长效注射用Zyprexa获准用于治疗精神分裂症成人患者
2009年12月14日，礼来公司宣布，美国食品药品管理局(FDA)已批准yprexa Relprevv (奥氮平)用于治疗精神分裂症成人患者。该长效抗精神病药通过肌注给药，可持续释放奥氮平达4周。
 
礼来公司在新闻发布会上称，应用长效药物Zyprexa Relprevv治疗精神分裂症的优势在于，可使精神科医生准确知道患者接受治疗的时间，并且如果患者未复诊接受预定注射的话，可立即发现患者对治疗不依从。
 
FDA批准Zyprexa Relprevv是基于涉及2,054例患者的临床数据。应用该药治疗后，精神分裂症患者的下列症状得到了控制，包括幻觉、妄想、情感淡漠和社交退缩。礼来公司表示，该药疗效明确，不需要口服补充治疗。
 
在研究中，Zyprexa Relprevv的给药剂量为150mg、210mg、300mg和405mg。根据剂量的不同，治疗性奥氮平暴露时间可维持2周或4周。
 
研究发现，除了注射相关事件(如注射后谵妄/镇静综合征，PDSS)之外，Zyprexa Relprevv的安全性与口服奥氮平相似。PDSS事件包括许多镇静体征和症状，从轻度镇静到昏迷和(或)谵妄，包括精神错乱、定向障碍、激越、焦虑或其他认知功能障碍。
 
截至2009年11月30日，在所有临床试验中，因注射Zyprexa Relprevv 而出现PDSS事件的几率<0.1%，约2%患者出现PDSS事件。注射后最初1h内出现事件的可能性最大。多数事件在注射后最初3h内出现；然而，也有事件在3h后才出现。所有出现PDSS事件的患者基本上可在72h内恢复，多数患者选择继续接受Zyprexa Relprevv治疗。Zyprexa Relprevv标签内容包括，要求在能够随时实施紧急救护的医疗机构对患者每次注射后进行至少3h的观察，并且在患者离开该医疗机构时安排专人陪同其前往其所要到达的目的地。
 
短期安慰剂对照试验报告的最常见治疗中出现的不良事件(treatment-emergent adverse events)(至少1个 Zyprexa Relprevv治疗组的发生率>5%，并高于安慰剂组)为头痛、镇静、体重增加、咳嗽、腹泻、腰痛、恶心、嗜睡、口干、鼻咽炎、食欲增加和呕吐。