EXOSURF®NEONATAL

葛兰素

Colfosceril棕榈酸酯

合成肺表面活性剂

行动和临床药理学：表面活性物质缺乏症是新生儿呼吸窘迫综合征（RDS）发展的重要因素。天然表面活性剂，脂质和脱辅基蛋白的组合，不仅表现出表面张力降低性质（由脂质赋予），而且还表现出快速铺展和吸附（由载脂蛋白赋予）。天然表面活性剂的脂质组分的主要部分是棕榈酸棕榈酸酯（也称为二棕榈酰磷脂酰胆碱或DPPC），其包含高达70重量％的天然表面活性剂。

尽管DPPC降低表面张力，但DPPC单独在RDS中无效，因为DPPC扩散和吸附性差。在不含蛋白质的Exosurf新生儿中，鲸蜡醇在气液界面上作为DPPC的扩散剂。 Tyloxapol是一种聚合长链重复醇，是一种非离子表面活性剂，用于分散DPPC和鲸蜡醇。加入氯化钠以调节渗透压。

临床研究：Exosurf新生儿曾在美国和加拿大进行过对照临床试验，涉及超过4 400名婴儿。

预防性治疗：在3项双盲，安慰剂对照研究中检查了单剂量的colfosceril预防性治疗患有呼吸窘迫综合征（RDS）风险的婴儿的疗效。对婴儿进行插管并放置机械通气，并在出生后30分钟内接受5mL / kg colfosceril或安慰剂（空气）。

另一项研究比较了1剂和3剂的colfosceril的疗效。婴儿进行插管并置于机械通气并在30分钟内接受第一次5mL / kg剂量的colfosceril。对大约12小时和24小时保持机械通气的所有婴儿重复5mL / kg剂量的colfosceril或安慰剂（空气）。

救援治疗：在2项双盲，安慰剂对照研究中检验了colfosceril在救治RDS婴儿中的疗效。在这些救援治疗研究中，婴儿在生命的2至24小时内接受了初始剂量（5 mL / kg）的colfosceril或安慰剂（空气），大约12小时后接受第二次剂量（5 mL / kg）给残留的婴儿在机械通气。

临床结果：在受控的预防和抢救研究中，colfosceril组的婴儿显示FiO2和呼吸机设置显着改善，持续至少7天。在每项研究中，肺漏气显着减少。其中四项研究也显示RDS死亡率显着下降。在700至1 100克婴儿中，1剂与3剂的预防性治疗研究显示总体死亡率进一步降低，另有2剂。

在2 470名存活婴儿中，有1 094名年龄调整后的随访资料。在这个样本中接受colfosceril的婴儿的生长和发育与接受安慰剂的婴儿相似。

药代动力学：Colfosceril直接注入气管。尚未进行Exosurf新生儿组分吸收，生物转化和排泄的人体药代动力学研究。然而，非临床研究表明，DPPC可以从肺泡吸收到肺组织中，在那里它可以被广泛分解代谢并用于进一步的磷脂合成和分泌。

适应症和临床用途：1.用于预防性治疗有发展成RDS风险或有肺不成熟证据的婴儿。

临床医生应仔细评估体重500至700克的婴儿使用colfosceril的潜在风险和益处。这些婴儿单次预防剂量显着改善FiO2和呼吸机设置，减少气胸，减少RDS死亡，但增加肺出血（见警告）。在这项研究中，安慰剂组和colfosceril组的总体死亡率没有显着差异。

对于预防性治疗，应在出生后尽快给予头孢菌素首剂（参见剂量，给药通用指南）。

2.对已开发RDS的婴儿进行抢救治疗。

考虑作为colfosceril抢救治疗候选对象的婴儿应该使用机械通气并根据以下两个标准诊断RDS：基于临床和实验室评估以及与诊断一致的胸部X线检查结果，不归因于RDS以外病因的呼吸窘迫的RDS。

禁忌症：没有已知的禁忌症治疗colfosceril。

制造商在临床状态下的警告：

仅限气管内给药：Colfosceril只能通过滴入气管进行给药（见剂量）。

一般情况：

使用colfosceril需要由经验丰富的新生儿专家和其他临床医师在新生儿插管和通气管理中完成临床护理。需要足够的人员，设施，设备和药物来优化早产儿围产期结局。

只应由训练有素的经验丰富的气道医生和不稳定早产儿的临床管理人员进行colfosceril滴注。在给予colfosceril之前，期间和之后，应对所有婴儿给予警惕的临床关注。

可能的即时影响：Colfosceril可以迅速影响氧合和肺顺应性。因此，如有指示，应按以下方式调整以下参数：肺顺应性：如果给药后胸腔扩张明显改善，应立即降低呼吸机峰值吸气压，而不必等待血气评估确认呼吸改善。如果在这种情况下未能迅速降低吸气呼吸机压力，可能会导致肺过度滞留和致命的肺部漏气。

高氧症：如果婴儿变成粉红色并且经皮血氧饱和度超过95％，则FiO2应该以小但重复的步骤（直至饱和度为90至95％）减少，而不等待通过血气评估确认升高的动脉pO2。在这种情况下未能减少FiO2可能导致高氧症。

低碳水化合物：如果动脉或经皮二氧化碳测量是

肺出血：对重达700 g的婴儿进行的单一研究中，安慰剂组婴儿中出现1％（14/1 420）婴儿肺出血，colfosceril组婴儿出现肺出血2％（27/1 411）。 3名婴儿发生致命性肺出血; colfosceril组2例，安慰剂组1例。发生肺出血的婴儿死亡率在安慰剂组为43％，colfosceril组为37％。

在较年轻，较小，男性或有动脉导管未闭的婴儿中，colfosceril和安慰剂婴儿的肺出血更频繁。在两个治疗组中，肺出血通常发生在生命的头两天。

在一项开放，不受控制的研究中，超过7 700名婴儿报告4％接受colfosceril治疗的婴儿出现肺出血，死亡率为0.4％。

在对照临床研究中，在出生前超过24小时接受类固醇或出生后消炎痛的接受colfosceril治疗的婴儿（出生体重> 700 g）与其他接受colfosceril治疗的婴儿相比肺出血率较低。应注意早期和积极的诊断和治疗（除非禁忌）动脉导管未闭在生命的头两天内（当动脉导管通常临床无症状时）。其他潜在的保护措施包括在给药后的最初24至48小时内试图优先降低FiO2超过呼吸机压力，并试图在给药后至少48小时降低最终呼气末正压（PEEP）。

黏液塞：给药期间或不久后通气显着受损的婴儿可能会气管插管粘液堵塞，特别是在给药前肺部分泌物显着的情况下。在给药之前吸入所有婴儿可以减少粘液塞阻塞气管内管的机会。如果怀疑气管插管阻塞了这种塞子，并且在取出时吸取不成功

预防措施：回流：已观察到给药期间colfosceril回流到气管内导管，可能与快速给药有关。如果发生反流，应停止给药，如有必要，呼吸机的吸气峰值压力应增加4至5 cm H2O，直至气管导管清除。

Ø 20％经皮氧饱和度下降：如果在给药期间经皮血氧饱和度下降，应停止给药，必要时呼吸机的吸气峰值压力应增加4至5 cm H2O 1至2分钟。另外，FiO2的增加可能需要1到2分钟。

Ø 

心率影响：在给药期间报道心动过缓（200次/分钟）。

呼吸暂停：在对照临床试验中接受colfosceril治疗的婴儿，与对照组婴儿相比，呼吸暂停的发生率较高，与甲基黄嘌呤治疗的使用增加有关。

不良反应：在评估colfosceril安全性和有效性的对照临床研究中，进行了许多安全性评估。在接受colfosceril的婴儿中，肺出血，呼吸暂停和甲基黄嘌呤的使用增加。 colfosceril组的一些其他不良事件明显减少，特别是各种形式的肺漏气和泮库溴铵的使用。

实验室异常值：实验室检查结果异常在重症机械通气早产儿中很常见。没有报道colfosceril组异常实验室值的发生率较高。

过量的症状和治疗：症状和治疗：没有关于colfosceril过量的报道。

剂量和给药方式：预防性治疗：出生后第一次应该以5毫升/公斤剂量单次给药。第二次和第三次给药应在大约12和24小时后给予在那些时间保持机械通气的所有婴儿。

救援治疗：Colfosceril应以两次5 mL / kg剂量给药。在确诊RDS后应尽快给予初始剂量。如果婴儿仍然处于机械通气状态，应在第一次给药后约12小时施用第二剂。

悬浮液的制备：Exosurf最好在使用前立即重新配制，因为它不含抗菌防腐剂。然而，重构的悬浮液在化学和物理上稳定并且在重建后在2和30℃之间储存长达12小时时保持无菌（当使用无菌技术重构时）。

含有缓冲液或防腐剂的溶液不应用于重建。不要使用抑菌水注射，USP。每个小瓶的colfosceril只能用8 mL无防腐剂的无菌注射用水重新配制，如下所示：

1.使用18号或19号针头向8毫升无防腐剂无菌注射用无菌注射器注入10毫升或12毫升注射器。

2.让小瓶中的真空将无菌水吸入小瓶中。

3.尽可能多地将重新混合的悬浮液从小瓶中吸入注射器（同时保持真空），然后突然松开注射器柱塞。重复3或4次以确保小瓶内容物充分混合。

如果不存在真空，则不应使用colfosceril的小瓶。

然后应将整个剂量（5mL / kg）的合适剂量体积从小瓶中的泡沫下方（再次保持真空）吸入注射器中。

重建Exosurf新生儿是一种乳白色混悬液，总体积为8 mL /瓶。每mL重建Exosurf含有13.5毫克棕榈酸毛果心油，1.5毫克鲸蜡醇，1毫克泰洛沙泊和氯化钠，以提供0.1N浓度。如果悬浮液似乎分开，轻轻摇动或旋动瓶重新悬浮制剂。应立即在施用前立即检查再造产品的均匀性;如果存在持久的大片或颗粒，则不应使用小瓶。

使用特殊的气管内插管适配器：应使用配备有特殊直角鲁尔锁边舱的气管插管适配器。作为Exosurf套件的一部分提供的适配器是干净但不消毒的。适配器应按以下方式使用：

1.选择与气管导管内径相对应的适配器尺寸。

2.用适度的推扭运动将适配器插入气管导管。

3.将呼吸回路“Y”连接到适配器。

4.从适配器侧面的端口上取下盖子。将装有药物的注射器连接到侧面。

5.完成给药后，取出注射器并重新填充侧面。

施用：在施用colfosceril之前应该吸入婴儿。

Colfosceril悬浮液通过特殊气管导管适配器上的侧端口进行施用，而不中断机械通气。

每种colfosceril剂量以两次2.5mL / kg半剂量给药。每个半剂量在最少1至2分钟内缓慢灌注（30至50次机械呼吸），并以小爆发时间进行定时吸入。在中线位置施用第一次2.5mL / kg半剂量后，在继续机械通气的同时，将婴儿的头部和躯干向右旋转45°30秒。在婴儿返回中线位置后，第二次2.5mL / kg半剂量以相同的方式给药至少1至2分钟。然后将婴儿的头部和躯干向左转45°30秒，同时继续机械通气，然后将婴儿转回到中线位置。这些操作允许重力协助colfosceril在肺部的分布。

在给药期间应该监测心率，颜色，胸部膨胀，面部表情，血氧计和气管导管通畅性和位置。如果心率减慢，婴儿变得昏暗或激动，经皮血氧饱和度下降超过15％，或colfosceril支持气管导管，应减慢或停止给药，如有必要，吸气峰压，呼吸机速率和/或FiO2出现。另一方面，肺功能的快速改善可能需要立即降低峰值吸气压力，呼吸机速率和/或FiO2（参见警告和关于给药的其他信息参见下文）。

除非需要临床需要，否则不应在服用colfosceril 2小时后进行吸痰。

一般管理指南：colfosceril的管理不应优先于危重婴儿的临床评估和稳定。

插管：在给予colfosceril之前，重要的是要确保气管导管尖端位于气管中，而不是在食管或右侧或左侧主干支气管中。在每次机械吸气时胸部和对称的胸部运动应在给药前确认，因为在2个腋窝应该有相同的呼吸音。在预防性治疗中，不需要延迟用于colfosceril的剂量以用于放射学证实气管内管尖端位置。在救援治疗中，如果至少一次胸片在最后一次插管后确认了气管导管尖端的正确位置，通常床边确认气管导管尖端的位置是足够的。如果气管导管尖端太低，某些肺部区域将保持不动。

监测：给药期间连续心电图和经皮血氧饱和度监测至关重要。在大多数预防性治疗的婴儿中，应该有可能在施用第一剂量的colfosceril之前启动这种监测。对于随后的预防性和所有救援剂量，给药期间的动脉血压监测也是非常需要的。在预防性和补救性给药之后，需要频繁的动脉血气采样以防止给药后的高氧和低碳水化合物（参见警告）。

给药期间的通气支持：5 mL / kg的剂量体积可能会通过气道的物理阻塞导致气体交换暂时性损害，特别是在呼吸机设置较低的婴儿中。因此，婴儿在给药期间可能会出现氧饱和度下降，特别是如果他们在给药前呼吸机设置较低。在给药期间，呼吸机的吸气峰压增加4到5 cm H2O 1到2分钟，可以很容易地克服这些瞬态效应。如有必要，FiO2也可以增加。对于特别脆弱或对外界刺激产生反应的婴儿，在给药前将吸气峰压增加4〜5 cmH2O和/或FiO2 20％可能会使氧合的任何暂时性恶化最小化。但是，在几乎所有情况下，应该可以在剂量完成的很短时间内使婴儿返回给药前环境。

给药后：在给药结束时，气管导管的位置应通过听取2个腋窝呼吸音的平均值来确定。应注意胸部扩张，颜色，经皮血氧饱和度和动脉血气。一些接受colfosceril和其他表面活性剂的婴儿会迅速改善肺顺应性，每分钟通气量和气体交换（见警告）。在给药后至少30分钟，经验丰富的临床医生持续关注床边是至关重要的。频繁的血气采样也是绝对必要的。肺功能的快速变化需要立即改变吸气峰压，通气速率和/或FiO2。

可用性和储存：每个小瓶包含：粉状棕榈酸酯棕榈酸酯108毫克。将一个10mL新生儿Exosurf小瓶（8mL填充小瓶），一个10mL无菌注射用水瓶和5个气管内插管适配器（2.5,3.0,3.5,4.0和4.5mm内径）装入一套试剂盒中。储存在15至30°C的干燥地方。

Important: The information below refers to medicines available in the United States that contain colfosceril.

Brand names: Exosurf
Drug class(es): lung surfactants

EXOSURF® NEONATAL

Glaxo Wellcome

Colfosceril Palmitate

Synthetic Lung Surfactant

Action And Clinical Pharmacology: Surfactant deficiency is an important factor in the development of the neonatal respiratory distress syndrome (RDS). Natural surfactant, a combination of lipids and apoproteins, exhibits not only surface tension reducing properties (conferred by the lipids), but also rapid spreading and adsorption (conferred by the apoproteins). The major fraction of the lipid component of natural surfactant is colfosceril palmitate (also known as dipalmitoylphosphatidylcholine or DPPC), which comprises up to 70% of natural surfactant by weight.

Although DPPC reduces surface tension, DPPC alone is ineffective in RDS because DPPC spreads and adsorbs poorly. In Exosurf Neonatal, which is protein-free, cetyl alcohol acts as a spreading agent for the DPPC on the air-fluid interface. Tyloxapol, a polymeric long-chain repeating alcohol, is a nonionic surfactant, which acts to disperse both DPPC and cetyl alcohol. Sodium chloride is added to adjust osmolality.

Clinical Studies: Exosurf Neonatal has been studied in the U.S. and Canada in controlled clinical trials involving more than 4 400 infants.

Prophylactic Treatment: The efficacy of a single dose of colfosceril in prophylactic treatment of infants at risk of developing respiratory distress syndrome (RDS) was examined in 3 double-blind, placebo-controlled studies. The infants were intubated and placed on mechanical ventilation, and received 5 mL/kg colfosceril or placebo (air) within 30 minutes of birth.

An additional study compared the efficacy of 1 versus 3 doses of colfosceril. Infants were intubated and placed on mechanical ventilation and received a first 5 mL/kg dose of colfosceril within 30 minutes. Repeat 5 mL/kg doses of colfosceril or placebo (air) were given to all infants who remained on mechanical ventilation at approximately 12 and 24 hours of age.

Rescue Treatment: The efficacy of colfosceril in the rescue treatment of infants with RDS was examined in 2 double-blind, placebo-controlled studies. In these rescue treatment studies, infants received an initial dose (5 mL/kg) of colfosceril or placebo (air) between 2 and 24 hours of life followed by a second dose (5 mL/kg) approximately 12 hours later to infants who remained on mechanical ventilation.

Clinical Results: In controlled prophylactic and rescue studies, infants in the colfosceril group showed significant improvements in FiO2 and ventilator settings which persisted for at least 7 days. Pulmonary air leaks were significantly reduced in each study. Four of these studies also showed a significant reduction in death from RDS. The 1 versus 3-dose prophylactic treatment study in 700 to 1 100 g infants showed a further reduction in overall mortality with 2 additional doses.

Follow-up data at 1 year adjusted age are available on 1 094 of 2 470 surviving infants. Growth and development of infants who received colfosceril in this sample were comparable to infants who received placebo.

Pharmacokinetics: Colfosceril is administered directly into the trachea. Human pharmacokinetic studies of the absorption, biotransformation, and excretion of the components of Exosurf Neonatal have not been performed. Nonclinical studies, however, have shown that DPPC can be absorbed from the alveolus into lung tissue where it can be catabolized extensively and reutilized for further phospholipid synthesis and secretion.

Indications And Clinical Uses: 1. For prophylactic treatment of infants who are at risk of developing RDS or who have evidence of pulmonary immaturity.

Clinicians should carefully evaluate the potential risks and benefits of colfosceril administration in infants weighing 500 to 700 g. A single prophylactic dose in these infants significantly improved FiO2 and ventilator settings, reduced pneumothorax, and reduced death from RDS, but increased pulmonary hemorrhage (see Warnings). In this study, overall mortality did not differ significantly between the placebo and colfosceril groups.

For prophylactic treatment, the first dose of colfosceril should be administered as soon as possible after birth (see Dosage, General Guidelines for Administration).

2. Rescue treatment of infants who have developed RDS.

Infants considered as candidates for rescue treatment with colfosceril should be on mechanical ventilation and have a diagnosis of RDS by both of the following criteria: respiratory distress not attributable to causes other than RDS based on clinical and laboratory assessments and chest radiographic findings consistent with the diagnosis of RDS.

Contra-Indications: There are no known contraindications to treatment with colfosceril.

Manufacturers’ Warnings In Clinical States: Intratracheal Administration Only: Colfosceril should be administered only by instillation into the trachea (see Dosage).

General: The use of colfosceril requires expert clinical care by experienced neonatologists and other clinicians who are accomplished at neonatal intubation and ventilatory management. Adequate personnel, facilities, equipment and medications are required to optimize perinatal outcome in premature infants.

Instillation of colfosceril should be performed only by trained medical personnel experienced in airway and clinical management of unstable premature infants. Vigilant clinical attention should be given to all infants prior to, during and after administration of colfosceril.

Possible Immediate Effects: Colfosceril can rapidly affect oxygenation and lung compliance. Therefore, when indicated, the following parameters should be adjusted as follows: Lung Compliance: If chest expansion improves substantially after dosing, peak ventilator inspiratory pressures should be reduced immediately, without waiting for confirmation of respiratory improvement by blood gas assessment. Failure to reduce inspiratory ventilator pressures rapidly in such instances can result in lung overdistention and fatal pulmonary air leak.

Hyperoxia: If the infant becomes pink and transcutaneous oxygen saturation is in excess of 95%, FiO2 should be reduced in small but repeated steps (until saturation is 90 to 95%) without waiting for confirmation of elevated arterial pO2 by blood gas assessment. Failure to reduce FiO2 in such instances can result in hyperoxia.

Hypocarbia: If arterial or transcutaneous CO2 measurements are
Pulmonary Hemorrhage: In the single study conducted in infants weighing 700 g, pulmonary hemorrhage was reported for 1% (14/1 420) of infants in the placebo group and 2% (27/1 411) of infants in the colfosceril group. Fatal pulmonary hemorrhage occurred in 3 infants; 2 in the colfosceril group and 1 in the placebo group. Mortality from all causes among infants who developed pulmonary hemorrhage was 43% in the placebo group and 37% in the colfosceril group.

Pulmonary hemorrhage in both colfosceril and placebo infants was more frequent in infants who were younger, smaller, male, or who had a patent ductus arteriosus. Pulmonary hemorrhage generally occurred in the first 2 days of life in both treatment groups.

In more than 7 700 infants in an open, uncontrolled study, pulmonary hemorrhage was reported in 4% of colfosceril-treated infants, with a fatality rate of 0.4%.

In the controlled clinical studies, colfosceril-treated infants (birth weights >700 g) who received steroids more than 24 hours prior to delivery or indomethacin postnatally had a lower rate of pulmonary hemorrhage than other colfosceril-treated infants. Attention should be paid to early and aggressive diagnosis and treatment (unless contraindicated) of patent ductus arteriosus during the first 2 days of life (when the ductus arteriosus is often clinically silent). Other potentially protective measures include attempting to decrease FiO2 preferentially over ventilator pressures during the first 24 to 48 hours after dosing, and attempting to decrease Positive End Expiratory Pressure (PEEP) minimally for at least 48 hours after dosing.

Mucous Plugs: Infants whose ventilation becomes markedly impaired during or shortly after dosing may have mucus plugging of the endotracheal tube, particularly if pulmonary secretions were prominent prior to drug administration. Suctioning of all infants prior to dosing may lessen the chance of mucous plugs obstructing the endotracheal tube. If endotracheal tube obstruction from such plugs is suspected, and suctioning is unsuccessful in removing the obstruction, the blocked endotracheal tube should be replaced immediately.

Precautions: Reflux: Reflux of colfosceril into the endotracheal tube during dosing has been observed and may be associated with rapid drug administration. If reflux occurs, drug administration should be halted and, if necessary, peak inspiratory pressure on the ventilator should be increased by 4 to 5 cm H2O until the endotracheal tube clears.

>20% Drop in Transcutaneous Oxygen Saturation: If transcutaneous oxygen saturation declines during dosing, drug administration should be halted and, if necessary, peak inspiratory pressure on the ventilator should be increased by 4 to 5 cm H2O for 1 to 2 minutes. In addition, increases of FiO2 may be required for 1 to 2 minutes.

Heart Rate Effects: Bradycardia (200 beats/min) have been reported during dosing.

Apnea: Infants treated with colfosceril in controlled clinical trials have been noted to have a higher incidence of apnea, associated with an increased use of methylxanthine therapy, than have infants in the control groups.

Adverse Reactions: In controlled clinical studies evaluating the safety and efficacy of colfosceril, numerous safety assessments were made. In infants receiving colfosceril, pulmonary hemorrhage, apnea and use of methylxanthines were increased. A number of other adverse events were significantly reduced in the colfosceril group, particularly various forms of pulmonary air leaks and use of pancuronium.

Abnormal Laboratory Values: Abnormal laboratory values are common in critically ill, mechanically ventilated, premature infants. A higher incidence of abnormal laboratory values in the colfosceril group was not reported.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There have been no reports of overdose with colfosceril.

Dosage And Administration: Prophylactic Treatment: The first dose should be administered as a single 5 mL/kg dose as soon as possible after birth. Second and third doses should be administered approximately 12 and 24 hours later to all infants who remain on mechanical ventilation at those times.

Rescue Treatment: Colfosceril should be administered in two 5 mL/kg doses. The initial dose should be administered as soon as possible after the diagnosis of RDS is confirmed. The second dose should be administered approximately 12 hours following the first dose, provided the infant remains on mechanical ventilation.

Preparation of Suspension: Exosurf is best reconstituted immediately before use because it does not contain antibacterial preservatives. However, the reconstituted suspension is chemically and physically stable and remains sterile (when reconstituted using aseptic techniques) when stored between 2 and 30°C for up to 12 hours following reconstitution.

Solutions containing buffers or preservatives should not be used for reconstitution. Do not use Bacteriostatic Water for Injection, USP. Each vial of colfosceril should be reconstituted only with 8 mL of preservative-free Sterile Water for Injection as follows:

1. Fill a 10 mL or 12 mL syringe with 8 mL preservative-free Sterile Water for Injection using an 18- or 19-gauge needle.

2. Allow the vacuum in the vial to draw the sterile water into the vial.

3. Aspirate as much as possible of the reconstituted suspension out of the vial into the syringe (while maintaining the vacuum), then suddenly release the syringe plunger. Repeat 3 or 4 times to ensure adequate mixing of the vial contents.

If vacuum is not present, the vial of colfosceril should not be used.

The appropriate dosage volume for the entire dose (5 mL/kg) should then be drawn into the syringe from below the froth in the vial (again maintaining the vacuum).

Reconstituted Exosurf Neonatal is a milky white suspension with a total volume of 8 mL/vial. Each mL of reconstituted Exosurf contains colfosceril palmitate 13.5 mg, cetyl alcohol 1.5 mg, tyloxapol 1 mg, and sodium chloride to provide a 0.1 N concentration. If the suspension appears to separate, gently shake or swirl the vial to resuspend the preparation. The reconstituted product should be inspected visually for homogeneity immediately before administration; if persistent large flakes or particulates are present, the vial should not be used.

Use of Special Endotracheal Tube Adapter: Endotracheal tube adapters equipped with a special right-angle Luer-lock sideport should be used. The adapters provided as part of the Exosurf kit are clean but not sterile. The adapters should be used as follows:

1. Select an adapter size which corresponds to the inside diameter of the endotracheal tube.

2. Insert the adapter into the endotracheal tube with a firm push-twist motion.

3. Connect the breathing circuit “Y” to the adapter.

4. Remove the cap from the sideport on the adapter. Attach the syringe containing drug to the sideport.

5. After completion of dosing, remove the syringe and recap the sideport.

Administration: The infant should be suctioned prior to administration of colfosceril.

Colfosceril suspension is administered via the sideport on the special endotracheal tube adaptor without interrupting mechanical ventilation.

Each colfosceril dose is administered in two 2.5 mL/kg half-doses. Each half-dose is instilled slowly over a minimum of 1 to 2 minutes (30 to 50 mechanical breaths) in small bursts timed with inspiration. After the first 2.5 mL/kg half-dose is administered in the midline position, the infant’s head and torso are turned 45° to the right for 30 seconds while mechanical ventilation is continued. After the infant is returned to the midline position, the second 2.5 mL/kg half-dose is given in an identical fashion over a minimum of 1 to 2 minutes. The infant’s head and torso are then turned 45° to the left for 30 seconds while mechanical ventilation is continued, and the infant is then turned back to the midline position. These manoeuvres allow gravity to assist in the distribution of colfosceril in the lungs.

Heart rate, color, chest expansion, facial expressions, the oximeter and the endotracheal tube patency and position should all be monitored during dosing. If heart rate slows, the infant becomes dusky or agitated, transcutaneous oxygen saturation falls more than 15%, or colfosceril backs up in the endotracheal tube, dosing should be slowed or halted and, if necessary, the peak inspiratory pressure, ventilator rate and/or FiO2 turned up. On the other hand, rapid improvements in lung function may require immediate reductions in peak inspiratory pressure, ventilator rate, and/or FiO2 (see Warnings and see below for additional information concerning administration).

Suctioning should not be performed for 2 hours after colfosceril is administered, except when dictated by clinical necessity.

General Guidelines for Administration: Administration of colfosceril should not take precedence over clinical assessment and stabilization of critically ill infants.

Intubation: Prior to dosing with colfosceril, it is important to ensure that the endotracheal tube tip is in the trachea and not in the esophagus or right or left mainstem bronchus. Brisk and symmetrical chest movement with each mechanical inspiration should be confirmed prior to dosing, as should equal breath sounds in the 2 axillae. In prophylactic treatment, dosing with colfosceril need not be delayed for radiographic confirmation of the endotracheal tube tip position. In rescue treatment, bedside confirmation of endotracheal tube tip position is usually sufficient, if at least one chest radiograph subsequent to the last intubation confirmed proper position of the endotracheal tube tip. Some lung areas will remain undosed if the endotracheal tube tip is too low.

Monitoring: Continuous ECG and transcutaneous oxygen saturation monitoring during dosing are essential. In most infants treated prophylactically, it should be possible to initiate such monitoring prior to administration of the first dose of colfosceril. For subsequent prophylactic and all rescue doses, arterial blood pressure monitoring during dosing is also highly desirable. After both prophylactic and rescue dosing, frequent arterial blood gas sampling is required to prevent post-dosing hyperoxia and hypocarbia (see Warnings).

Ventilatory Support During Dosing: The 5 mL/kg dosage volume may cause transient impairment of gas exchange by physical blockage of the airway, particularly in infants on low ventilator settings. As a result, infants may exhibit a drop in oxygen saturation during dosing, especially if they are on low ventilator settings prior to dosing. These transient effects are easily overcome by increasing peak inspiratory pressure on the ventilator by 4 to 5 cm H2O for 1 to 2 minutes during dosing. FiO2 can also be increased if necessary. In infants who are particularly fragile or reactive to external stimuli, increasing peak inspiratory pressure by 4 to 5 cm H2O and/or FiO2 20% just prior to dosing may minimize any transient deterioration in oxygenation. However, in virtually all cases it should be possible to return the infant to pre-dosing settings within a very short time of dose completion.

Post-Dosing: At the end of dosing, position of the endotracheal tube should be confirmed by listening for equal breath sounds in the 2 axillae. Attention should be paid to chest expansion, color, transcutaneous oxygen saturation, and arterial blood gases. Some infants who receive colfosceril and other surfactants respond with rapid improvements in pulmonary compliance, minute ventilation, and gas exchange (see Warnings). Constant bedside attention of an experienced clinician for at least 30 minutes after dosing is essential. Frequent blood gas sampling also is absolutely essential. Rapid changes in lung function require immediate changes in peak inspiratory pressure, ventilatory rate and/or FiO2.

Availability And Storage: Each vial contains: colfosceril palmitate 108 mg in a powder form. Kits of one 10 mL vial of Exosurf Neonatal (8 mL Fill Vial), one 10 mL vial of Sterile Water for Injection and 5 endotracheal tube adapters (2.5, 3.0, 3.5, 4.0 and 4.5 mm I.D.). Store between 15 and 30°C in a dry place.