7月26日MedImmune公司宣布，美国FDA已经批准该公司帕利珠单抗（palivizumab，Synagis）新型注射液上市
Synagis是一种人源化的单克隆抗体，于1998年获FDA批准用于防止呼吸道合胞病毒（RSV）感染高危婴幼儿因RSV而引起的严重下呼吸道疾病。Synagis是首个获准用于防止此类感染的单克隆抗体，也是该类药物中首个可以安全用于儿科患者的药物。
RSV感染是婴幼儿和儿童中最常见的呼吸道感染，其在美国每年导致125000例1岁以下婴幼儿住院。约有半数婴幼儿会在出生后的第一年中受到RSV感染，几乎所有婴幼儿会在2周岁之前至少感染1次。早产儿、慢性肺疾病患儿和先天性心脏病患儿是RSV感染的高危人群。
Synagis被批准用于防止高危婴幼儿因RSV引起的严重下呼吸道感染，其用药方式为肌内注射，在RSV高发季节一月注射1次。
新型Synagis注射液的上市给医务工作者、患儿家长以及患儿都带来了方便。Synagis最初获准的剂型是注射用冻干剂，使用时需要先将其用无菌水溶解，此过程需要20分钟，而且配制成注射液后必须在6小时内使用。而新的Synagis注射液免去了以往使用冻干剂时所需的配制步骤，也减少了患儿等候的时间。
分类名称
一级分类：生物制品、生化药物、酶及辅酶类 二级分类：疫苗 三级分类：
药品英文名
Palivizumab
药品别名
帕利佐单抗、帕利珠单抗、Synagis
药物剂型
注射剂：50mg；100mg。
药理作用
本品为呼吸道合胞病毒融合蛋白(F蛋白)的人单克隆抗体，对A亚型及B亚型等呼吸道合胞病毒临床分离株具有活性。体外实验表明其作用优于呼吸道合胞病毒多克隆免疫球蛋白(约高100倍)。
药动学
本品肌注后可在48h内达稳态血药浓度，1月给药1次，药物血清谷浓度随给药次数增加而升高。肌注或静脉给药的半衰期均为13～27日(接近IgG的半衰期)。
适应证
用于预防小儿呼吸道合胞病毒(RSV)感染。
禁忌证
对本品严重过敏者禁用。
注意事项
1．使用本品有轻微过敏反应者慎用。
2．定期使用本品，可降低高危儿童(包括慢性肺部疾病、严重先天性心脏病、早产儿等)呼吸道合胞病毒感染的住院率。
3．本品的妊娠安全性分级为C级。
4．药物对哺乳的影响尚不明确。
5．必要时应检查呼吸道合胞病毒抗原。
6．本品主要用于儿童呼吸道合胞病毒感染的预防，不适用于感染后的治疗。
7．肌内注射用量大于1ml时应分次给药。
8．本品溶解后应在6h内使用。
9．于2～8℃保存。
不良反应
1．呼吸系统：可有鼻炎、咽炎、喘息、咳嗽等上呼吸道感染症状。
2．肝脏：有肝功能异常的报道，如丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)升高等。
3．胃肠道：有出现腹泻、呕吐的报道。
4．过敏反应：本品引起的过敏反应较少见。
5．其他：肌注可引起注射部位反应及皮疹。有使用本品引起发热的报道。
用法用量
肌注。
1．预防高危儿童呼吸道合胞病毒感染常在病毒流行季节给药，第一次给药多在流行开始之前(通常为11月初)，一次15mg/kg，1个月1次，最多可给药5次。
2．施行心肺分流术的患儿由于心肺分流术后本品血药浓度可下降约58%，术后应给药以维持有效血药浓度。
药物相应作用
尚不明确。

SYNAGIS ® (PALIVIZUMAB)
for Intramuscular Administration                                          
Rx only
DESCRIPTION:

Synagis (palivizumab) is a humanized monoclonal antibody (IgG1κ) produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the F protein of respiratory syncytial virus (RSV). Synagis is a composite of human (95%) and murine (5%) antibody sequences. The human heavy chain sequence was derived from the constant domains of human IgG1 and the variable framework regions of the VH genes Cor (1) and Cess (2). The human light chain sequence was derived from the constant domain of Cκ and the variable framework regions of the VL gene K104 with Jκ -4 (3). The murine sequences were derived from a murine monoclonal antibody, Mab 1129 (4), in a process that involved the grafting of the murine complementarity determining regions into the human antibody frameworks. Synagis is composed of two heavy chains and two light chains and has a molecular weight of approximately 148,000 Daltons.
Synagis is supplied as a sterile, preservative-free liquid solution at 100 mg/mL to be administered by intramuscular injection (IM). Thimerosal or other mercury containing salts are not used in the production of Synagis. The solution has a pH of 6.0 and should appear clear or slightly opalescent.
Each 100 mg single-dose vial of Synagis liquid solution contains 100 mg of Synagis, 3.9 mg of histidine, 0.1 mg of glycine, and 0.5 mg of chloride in a volume of 1 mL.
Each 50 mg single-dose vial of Synagis liquid solution contains 50 mg of Synagis, 1.9 mg of histidine, 0.06 mg of glycine, and 0.2 mg of chloride in a volume of 0.5 mL.
CLINICAL PHARMACOLOGY:
Mechanism of Action :
Synagis exhibits neutralizing and fusion-inhibitory activity against RSV. These activities inhibit RSV replication in laboratory experiments. Although resistant RSV strains may be isolated in laboratory studies, a panel of 57 clinical RSV isolates were all neutralized by Synagis (5). Synagis serum concentrations of ≥ 40 mcg/mL have been shown to reduce pulmonary RSV replication in the cotton rat model of RSV infection by 100-fold (5). The in vivo neutralizing activity of the active ingredient in Synagis was assessed in a randomized, placebo-controlled study of 35 pediatric patients tracheally intubated because of RSV disease. In these patients, Synagis significantly reduced the quantity of RSV in the lower respiratory tract compared to control patients (6).
Pharmacokinetics :
In pediatric patients < 24 months of age without congenital heart disease (CHD), the mean half-life of Synagis was 20 days and monthly intramuscular doses of 15 mg/kg achieved mean ±SD 30 day trough serum drug concentrations of 37 ± 21 mcg/mL after the first injection, 57 ± 41 mcg/mL after the second injection, 68 ± 51 mcg/mL after the third injection and 72 ± 50 mcg/mL after the fourth injection (7). Trough concentrations following the first and fourth Synagis dose were similar in children with CHD and in non-cardiac patients. In pediatric patients given Synagis for a second season, the mean ±SD serum concentrations following the first and fourth injections were 61 ± 17 mcg/mL and 86 ± 31mcg/mL, respectively.
In 139 pediatric patients ≤ 24 months of age with hemodynamically significant CHD who received Synagis and underwent cardio-pulmonary bypass for open-heart surgery, the mean ±SD serum Synagis concentration was 98 ± 52 mcg/mL before bypass and declined to 41 ± 33 mcg/mL after bypass, a reduction of 58% (see DOSAGE AND ADMINISTRATION ). The clinical significance of this reduction is unknown.
Specific studies were not conducted to evaluate the effects of demographic parameters on Synagis systemic exposure. However, no effects of gender, age, body weight or race on Synagis serum trough concentrations were observed in a clinical study with 639 pediatric patients with CHD (≤24 months of age) receiving five monthly intramuscular injections of 15 mg/kg of Synagis.
The pharmacokinetics and safety of Synagis liquid solution and Synagis lyophilized formulation administered IM at 15 mg/kg were studied in a cross-over trial of 153 pediatric patients ≤6 months of age with a history of prematurity. The results of this trial indicated that the trough serum concentrations of palivizumab were comparable between the liquid solution and the lyophilized formulation, which was the formulation used in the clinical studies described below.
CLINICAL STUDIES:
The safety and efficacy of Synagis were assessed in two randomized, double-blind, placebo-controlled trials of prophylaxis against RSV infection in pediatric patients at high risk of an RSV-related hospitalization. Trial 1 was conducted during a single RSV season and studied a total of 1,502 patients ≤ 24 months of age with bronchopulmonary dysplasia (BPD) or infants with premature birth (≤ 35 weeks gestation) who were ≤ 6 months of age at study entry (7). Trial 2 was conducted over four consecutive seasons among a total of 1287 patients ≤ 24 months of age with hemodynamically significant congenital heart disease. In both trials participants received 15 mg/kg Synagis or an equivalent volume of placebo IM monthly for five injections and were followed for 150 days from randomization. In Trial 1, 99% of all subjects completed the study and 93% completed all five injections. In Trial 2, 96% of all subjects completed the study and 92% completed all five injections. The incidence of RSV hospitalization is shown in Table 1.

Table 1: Incidence of RSV Hospitalization by Treatment Group

Trial		Placebo	Synagis	Difference Between Groups	Relative Reduction	p-Value
Trial 1 Impact-RSV	N	500	1002
	Hospitalization	53 (10.6%)	48 (4.8%)	5.8%	55%	<0.001
Trial 2 CHD	N	648	639
	Hospitalization	63 (9.7%)	34 (5.3%)	4.4%	45%	0.003

In Trial 1, the reduction of RSV hospitalization was observed both in patients with BPD (34/266 [12.8%] placebo vs. 39/496 [7.9%] Synagis), and in premature infants without BPD (19/234 [8.1%] placebo vs. 9/506 [1.8%] Synagis). In Trial 2, reductions were observed in acyanotic (36/305 [11.8%] placebo versus 15/300 [5.0%] Synagis) and cyanotic children (27/343 [7.9%] placebo versus 19/339 [5.6%] Synagis).
The clinical studies do not suggest that RSV infection was less severe among RSV hospitalized patients who received Synagis compared to those who received placebo.
INDICATIONS AND USAGE:
Synagis is indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients at high risk of RSV disease. Safety and efficacy were established in infants with bronchopulmonary dysplasia (BPD), infants with a history of premature birth (≤ 35 weeks gestational age), and children with hemodynamically significant congenital heart disease (CHD) (see  CLINICAL STUDIES ).
CONTRAINDICATIONS:
Synagis should not be used in pediatric patients with a history of a severe prior reaction to Synagis or other components of this product.
WARNINGS:
Cases of anaphylaxis and anaphylactic shock, including fatal cases, have been reported following initial exposure or re-exposure to Synagis. Severe acute hypersensitivity reactions have also been reported on initial exposure or re-exposure to Synagis. Symptoms may include dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, hypotonia, hypotension, and unresponsiveness. The relationship between these reactions and the development of antibodies to Synagis is unknown. If a severe hypersensitivity reaction occurs, therapy with Synagis should be permanently discontinued. If milder hypersensitivity reactions occur, caution should be used on readministration of Synagis. If anaphylaxis or severe allergic reactions occur, administer appropriate medications (e.g., epinephrine) and provide supportive care as required.
PRECAUTIONS:
General:
Synagis is for intramuscular use only. As with any intramuscular injection, Synagis should be given with caution to patients with thrombocytopenia or any coagulation disorder.
The safety and efficacy of Synagis have not been demonstrated for treatment of established RSV disease.
The single-dose vial of Synagis does not contain a preservative. Administration of Synagis should occur immediately after dose withdrawal from the vial. The vial should not be re-entered. Discard any unused portion.
Drug Interactions:
No formal drug-drug interaction studies were conducted. In Trial 1, the proportions of patients in the placebo and Synagis groups who received routine childhood vaccines, influenza vaccine, bronchodilators or corticosteroids were similar and no incremental increase in adverse reactions was observed among patients receiving these agents.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis, mutagenesis and reproductive toxicity studies have not been performed.
Pregnancy:
Pregnancy Category C:
Synagis is not indicated for adult usage and animal reproduction studies have not been conducted. It is also not known whether Synagis can cause fetal harm when administered to a pregnant woman or could affect reproductive capacity.
ADVERSE REACTIONS:
The most serious adverse reactions occurring with Synagis treatment are anaphylaxis and other acute hypersensitivity reactions (see WARNINGS ). The adverse reactions most commonly observed in Synagis-treated patients were upper respiratory tract infection, otitis media, fever, rhinitis, rash, diarrhea, cough, vomiting, gastroenteritis, and wheezing. Upper respiratory tract infection, otitis media, fever, and rhinitis occurred at a rate of 1% or greater in the Synagis group compared to placebo (Table 2).
Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information does, however, provide a basis for identifying the adverse events that appear to be related to drug use and a basis for approximating rates.
The data described reflect Synagis exposure for 1641 pediatric patients of age 3 days to 24.1 months in Trials 1 and 2. Among these patients, 496 had bronchopulmonary dysplasia, 506 were premature birth infants less than 6 months of age, and 639 had congenital heart disease. Adverse events observed in the 153 patient crossover study comparing the liquid and lyophilized formulations were similar between the two formulations, and similar to the adverse events observed with Synagis in Trials 1 and 2.

Table 2: Adverse Events Occurring at a Rate of 1% or Greater More Frequently in Patients^† Receiving Synagis

Event	Synagis (n=1641) n (%)	Placebo (n=1148) n (%)
Upper respiratory infection	830 (50.6)	544 (47.4)
Otitis media	597 (36.4)	397 (34.6)
Fever	446 (27.1)	289 (25.2)
Rhinitis	439 (26.8)	282 (24.6)
Hernia	68 (4.1)	30 (2.6)
SGOT Increase	49 (3.0)	20 (1.7)
Cyanosis (Synagis [9.1%]/placebo [6.9%]) and arrhythmia (Synagis [3.1%]/placebo [1.7%]) were reported during Trial 2 in CHD patients.