美国FDA批准新药Rexulti治疗精神分裂症和作为一种添加至一种抗抑郁剂治疗重性抑郁症
Rexulti是一种每日一次的口服药物，由大冢发现，由灵北和大冢联合开发。去年7月，FDA已批准Rexulti：(1)作为一种辅助药物用于重度抑郁症(MDD)成人患者的治疗;(2)用于精神分裂症(schizophrenia)成人患者的治疗。
FDA的药品评价和研究中心精神产品部门主任说：“精神分裂症和重性抑郁症可以能致残和可能大大地破坏天-天活动，”“药物对每个人影响不同所以重要的是对精神疾病患者可得到各种各样治疗选择。”
批准日期： 2015年7月10日；公司：大冢制药有限公司和H. Lundbeck A/S
REXULTI®（暂译名依匹哌唑 brexpiprazole）片剂，供于口服使用
最初美国批准：2015年
警告：
增加死亡率与老年痴呆症相关精神病老年住院患者;和自杀想法和行为，请参阅完整的黑框警告完整的处方信息。
•老年痴呆患者相关精神病用抗精神病药物治疗是在死亡的风险增加。 REXULTI未被批准用于治疗患有老年痴呆症相关的精神病治疗。
•抗抑郁药增加自杀想法和行为的风险
患者年龄24岁以下。监测临床恶化，自杀念头和行为的出现。
•REXULTI的安全性和有效性尚未确定在儿科患者。
作用机理
在抑郁症或精神分裂症的治疗brexpiprazole的作用机制是未知的。然而，brexpiprazole的德功效可以通过部分激动剂活性的组合在血清素5-HT 1A和多巴胺D2受体和拮抗剂活性在血清素5-HT 2A受体介导的。
适应症和用法
REXULTI是非典型抗精神病药指示为：
•使用作为一种辅助治疗抗抑郁药用于重度抑郁症的治疗（MDD）
•精神分裂症治疗。
用法用量
•每日一次辖REXULTI带或不带食物。
•中度至重度肝功能受损（Child-Pugh评分≥7）：最大推荐剂量是2毫克，每日一次，患者MDD和3毫克，每天一次为精神分裂症患者。
•中度，重度或终末期肾脏损害（CLCR <60毫升/分钟）：最大推荐剂量是2毫克，每日一次，患者MDD和3毫克，每天一次为精神分裂症患者。
•已知CYP2D6弱代谢：减少一半的常用剂量。
剂型和规格
片剂：0.25毫克，0.5毫克，1毫克，2毫克，3毫克和4毫克
禁忌症
已知过敏的任何成份或REXULTI。
警告和注意事项
•老年患者脑血管不良反应痴呆相关精神病：脑血管不良反应的发生率增加（E. G.中风，短暂性脑缺血发作）
•抗精神病药物恶性症候群：与立即停止并密切监测管理。
•迟发性运动障碍：如果停止临床适宜。
•代谢变化：监测血糖/糖尿病，血脂异常和体重增加。
•白细胞减少，中性粒细胞减少，粒细胞缺乏症和：执行患者全血细胞计数（CBC）与现有的前低白细胞计数（WBC）或白细胞减少或中性粒细胞减少史。试想，如果在WBC临床显著跌幅出现没有其他致病因素停止REXULTI。
•体位性低血压和晕厥：监视心脏速率和血压，并警告病人患有心血管或脑血管疾病，脱水或晕厥的危险。
•发作：患者谨慎使用有惊厥史或与条件，并降低癫痫发作阈值。
不良反应
最常见的不良反应为：
MDD：体重增加和静坐不能（≥5％和至少两次安慰剂率）
精神分裂症：重增加（≥4％和至少两次安慰剂率）
药物相互作用
影响因素：

在使用特定人群
妊娠：可能引起锥体外系和/或戒断症状与孕晚期暴露新生儿。
包装规格[注：采购以在线咨询为准]
REXULTI TAB 25MG 30  BREXPIPRAZOLE     59148-0035-13
REXULTI TAB 50MG 30  BREXPIPRAZOLE     59148-0036-13
REXULTI TAB 1MG 30   BREXPIPRAZOLE     59148-0037-13
REXULTI TAB 2MG 30   BREXPIPRAZOLE     59148-0038-13
REXULTI TAB 3MG 30   BREXPIPRAZOLE     59148-0039-13
REXULTI TAB 4MG 30   BREXPIPRAZOLE     59148-0040-13 

FDA approves Rexulti (brexpiprazole) as adjunctive treatment for adults with major depressive disorder and as a treatment for adults with schizophrenia
•There are approximately 15 million adults in the US with major depressive disorder (MDD), and many of them have an inadequate response to monotherapy with antidepressants. There are 2.4 million adults with schizophrenia in the US, many of whom continue to need effective treatmentsi
•The US approval of Rexulti is based on a clinical program in which Rexulti showed improvement vs. placebo in symptoms when used as an adjunctive therapy in MDD and as monotherapy in schizophrenia
•Rexulti will become available to patients in the US in early August 2015
US Food and Drug Administration (FDA) approved Rexulti® (brexpiprazole) as an adjunctive therapy for the treatment of adults with major depressive disorder (MDD) and as a treatment for adults with schizophrenia. Rexulti was discovered by Otsuka and co-developed with Lundbeck. It will be co-marketed by the two companies and is expected to become available to patients in the US in early August 2015. 
The mechanism of action of Rexulti in the treatment of MDD or schizophrenia is unknown. However, the efficacy of Rexulti may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors. In addition, Rexulti exhibits high affinity (subnanomolar) for these receptors, as well as for noradrenaline alpha1B/2C receptors. 
Rexulti was studied in more than 4,300 subjects in phase II and III clinical trials, and the approval was supported by four completed placebo-controlled clinical phase III studies in the now-approved indications — two studies as adjunctive therapy to antidepressants in MDD and two studies in schizophrenia.
Rexulti as MDD adjunctive treatment in adults
"For some patients with MDD, antidepressant monotherapy is not enough, and these patients continue to suffer from unresolved symptoms," said Michael E. Thase, MD, Professor of Psychiatry, Director, Mood and Anxiety Program, University of Pennsylvania School of Medicine and study investigator. "In the clinical trials that led to the FDA's approval, adding brexpiprazole to ongoing antidepressant therapy helped MDD patients improve unresolved symptoms of MDD."
As adjunctive therapy for MDD, the efficacy of Rexulti was evaluated in two, 6-week, placebo-controlled clinical trials of adult patients. Patients met the DSM-IV-TR criteria for MDD, with or without symptoms of anxiety, and previously failed to reach an adequate response during one to three treatment attempts with antidepressant therapy (ADT), and further failed to reach adequate response in a single-blind ADT phase for 8 weeks. The primary endpoint for both studies was change in MADRS (Montgomery—Åsberg Depression Rating Scale). Data from the clinical trials showed:
•Rexulti + ADT at 2 mg and 3 mg was superior to placebo; the mean baseline MADRS score decreased from 27 at randomization by 8.36 (2 mg) and 8.29 (3 mg), compared to placebo + ADT reductions of 5.15 and 6.33 in the respective studies; the 1 mg dose was not superior to placebo.
•Discontinuation due to adverse reactions was 3% for Rexulti + ADT compared with 1% for placebo + ADT. The most common adverse reactions for the pooled doses of adjunctive Rexulti + ADT (at least 5% and with twice the incidence of placebo), included akathisia (9% vs. 2% for placebo), and weight increase (7% vs. 2% for placebo).
Antidepressants increased the risk compared to placebo of suicidal thoughts and behavior in patients aged 24 years and younger in short-term studies. All antidepressant-treated patients should be monitored for clinical worsening, and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. 
Rexulti as schizophrenia treatment in adults
 "One key priority for physicians is to find medications that help improve symptoms and are tolerable for patients," said Dr. Christoph U. Correll, Professor of Psychiatry, Hofstra North Shore LIJ School of Medicine and Medical Director, Recognition and Prevention Program (RAP), The Zucker Hillside Hospital, both in New York, and lead author of one of the study reports. "In the Rexulti clinical trials for schizophrenia, we saw a combination of efficacy and symptom improvement within a tight target dose range with one adverse event, weight increase, occurring in at least 4% of patients and with twice the incidence of placebo."
The efficacy of Rexulti was established in two, 6-week, phase III randomized, placebo-controlled clinical trials with fixed doses of Rexulti vs. placebo. Clinical trial data showed:
•Rexulti, at an adequate dose for 6 weeks, demonstrated statistically significant efficacy for the primary endpoint of PANSS (Positive and Negative Syndrome Scale)
•In one trial, change from baseline in PANSS total score for Rexulti at both 2 mg/day and 4 mg/day (-20.73 and -19.65) was superior to placebo (-12.01); in a second trial, the change from baseline in PANSS total score at a dose of 4 mg/day (-20.00 vs. -13.53, respectively) was superior to placebo (2 mg was not superior to placebo in this trial)
•The most common adverse reactions (incidence of 4% or greater, and twice the incidence of placebo) from the pooled safety data associated with Rexulti at 1, 2 and 4 mg vs. placebo, included weight gain (4% vs. 2%, respectively)
•The incidence of somnolence (also including sedation and hypersomnia) in all patients with schizophrenia who received Rexulti (n=1,256) was 4.9% compared to 3.2% for patients receiving placebo (n=463).
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death compared to placebo (4.5% vs 2.6%, respectively). Although the causes of death were varied, most of the deaths appeared to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
"Psychiatric diseases remain a challenging therapeutic area where many people are unsatisfied with their treatments," noted Tatsuo Higuchi, President and Representative Director, Otsuka Pharmaceutical, Co., Ltd. "Today's approval of Rexulti is another example of Otsuka and Lundbeck's commitment to bringing new therapeutic alternatives to the mental health community."
"All treatment options require healthcare providers, patients and caregivers to balance efficacy and tolerability in managing their diseases," said Kåre Schultz, President and CEO, Lundbeck. "We are proud to introduce Rexulti to help adult patients living with MDD and schizophrenia."
Rexulti will become available to patients in the US in early August 2015. It is given in a once-daily oral dose with a well-defined titration schedule that can be taken with or without food.
•MDD: Initiate treatment at 0.5 g or 1 mg once daily. Titrate at weekly intervals to 1 mg once daily, then up to the target dosage of 2 mg once daily based on the patient's clinical response and tolerability
•Schizophrenia: Initiate treatment at 1 mg once daily for the first 4 days. Titrate to 2 mg once daily on Day 5 through Day 7, then to 4 mg on Day 8 based on the patient's clinical response and tolerability
•Specific dosage adjustments for inhibitors and inducers of the metabolism of Rexulti are described in the USPI
INDICATIONS and IMPORTANT SAFETY INFORMATION for REXULTI® (brexpiprazole)
INDICATIONS
REXULTI is indicated for:
•Use as an adjunctive therapy to antidepressants in adults with major depressive disorder
•Treatment of schizophrenia in adults
IMPORTANT SAFETY INFORMATION
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death compared to placebo (4.5% vs 2.6%, respectively). Although the causes of death were varied, most of the deaths appeared to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. REXULTI is not approved for the treatment of patients with dementia-related psychosis.
Suicidal Thoughts and Behaviors
Antidepressants increased the risk compared to placebo of suicidal thoughts and behavior in patients aged 24 years and younger in short-term studies. All antidepressant-treated patients should be monitored for clinical worsening, and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes.  Families and caregivers should be advised of the need for close observation for changes in behavior and to alert the healthcare provider. The safety and efficacy of REXULTI has not been established in pediatric patients with depression.
See Full Prescribing Information for complete Boxed WARNING
Contraindication: Known hypersensitivity reaction to REXULTI or any of its components.  Reactions have included: rash, facial swelling, urticaria and anaphylaxis.
Cerebrovascular Adverse Events, Including Stroke: In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated patients.
Neuroleptic Malignant Syndrome (NMS): A potentially fatal complex sometimes referred to as NMS has been associated with the administration of antipsychotic drugs. NMS can cause 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 creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems.
Tardive Dyskinesia (TD): The risk of developing TD and the potential for it to become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic increase. The syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing should be consistent with the need to minimize TD. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include:
•Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics.  There have been reports of hyperglycemia in patients treated with REXULTI.  Patients with diabetes should be regularly monitored for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood glucose testing. 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 should also undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the atypical antipsychotic drug.
•Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
•Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia, neutropenia, and agranulocytosis have been reported temporally related to atypical antipsychotics. Patients with history of a clinically significant low white blood cell (WBC) count or drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of REXULTI should be considered at the first sign of a clinically significant decline in WBC count in the absence of other causative factors.
Orthostatic Hypotension and Syncope: REXULTI may be associated with orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension.
Seizures: As with other antipsychotic drugs, REXULTI should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.
Body Temperature Dysregulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotics. Appropriate care is advised for patients who may exercise strenuously, be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or be subject to dehydration.
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.  REXULTI should be used with caution in patients at risk for aspiration pneumonia.
Potential for Cognitive and Motor Impairment: Like other antipsychotics, REXULTI may have the potential to impair judgment, thinking or motor skills. Patients should not drive or operate hazardous machinery until they are certain REXULTI does not affect them adversely.
Alcohol: Physicians should advise patients to avoid alcohol while taking REXULTI.
Concomitant Medication: Administer half the dose of REXULTI with strong CYP2D6 or CYP3A4 inhibitors.  Administer a quarter of the dose with strong/moderate CYP2D6 inhibitors or known CYP2D6 poor metabolizers or with strong/moderate CYP3A4 inhibitors. Double the dose with strong CYP3A4 inducers over 1 to 2 weeks.
In clinical trials examining the adjunctive use of REXULTI in the treatment of MDD, dosage was not adjusted for strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine).  CYP considerations were already factored into general dosing recommendations for MDD. Thus, REXULTI may be administered without dosage adjustment in these patients.
Most commonly observed adverse reactions: Adult patients with major depressive disorder (adjunctive treatment to antidepressant therapy; ≥5% incidence and twice incidence of placebo for REXULTI vs. placebo, respectively): akathisia (9% vs. 2%) and weight increase (7% vs. 2%).  Adult patients with schizophrenia (≥4% incidence and twice incidence of placebo for REXULTI vs. placebo, respectively): weight increased (4% vs. 2%)
Dystonia: Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses. 
Pregnancy: Non-Teratogenic Effects — Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. These complications have varied in severity, from being self-limited to requiring prolonged hospitalization. REXULTI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: It is not known if REXULTI is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Please see accompanying FULL PRESCRIBING INFORMATION, including Boxed WARNING, for REXULTI (brexpiprazole).
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2d301358-6291-4ec1-bd87-37b4ad9bd850