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· 【产品名称】猪肺磷脂注射液

· 【商品名/商标】

固尔苏

· 【规格】3ml:0.24g

· 【主要成份】猪肺磷脂注射液(固尔苏)主要成分为猪肺磷脂。

· 【适应症】

预防治疗早产婴儿呼吸窘迫综合征(RDS)。

· 【用法用量】推荐剂量为首剂100-200 mg/kg体重，气管内滴注。可以根据临床情况，再次给予1-2次重复剂量，每次给予100mg/kg体重，且2次剂量间隔12小时。一旦诊断呼吸窘迫综合征，应尽早应用此药。

· 【不良反应】目前未见副作用的报道。

· 【注意事项】本品使用前须先加温到37°C，并上下转动药瓶以使药液混合均匀。将一次剂量(100-200 mg/kg体重)药液沿气管插管直接滴注入下部气管。给药后行1分钟手工通气，给氧浓度须与给药前机械通气时的氧浓度一致。注入给药后也可立即行机械通气，使本药在肺内分布。给药后将患儿联入机械通气机时的起始设置须与给药前相一致。然后根据患儿临床状态和血气分析及时调节呼吸机设置。由于给药后血氧分压PaO2和血氧饱和度可以迅速提高，有必要密切观察动脉血气的变化。为防止高氧的危险，有必要连续监测经皮氧分压和氧饱和度。本品只可在医院内由对早产婴儿医护和复苏训练有素、经验丰富的临床医师使用。病房内应有对婴儿机械通气及监测的设施。

· 【药理毒理】本品是由猪肺的肺泡表面来源制备的一种天然表面活性物质，主要含有磷脂，特别是磷脂酰胆碱(占总磷脂的大约70%)和大约1-2%的表面活性物质特异疏水性低分子量蛋白SP-B和SP-C。肺表面活性物质是一种混合物，以磷脂和特异性蛋白为主组成，内衬于肺泡表面并降低肺泡表面张力。这一作用使得肺泡在呼气末保持扩张而不致塌陷，并且在整个呼吸周期维持充分气体交换。无论何种原因所致肺表面活性物质缺乏，都可以造成严重呼吸衰竭，被称为呼吸窘迫综合征(RDS)或肺透明膜病(HMD)。早产婴儿出生后第一天的发病及死亡原因主要是呼吸窘迫综合征，而且可以带来长期的呼吸和神经系统的后遗症。本药的开发应用，系将外源性肺表面活性物质制剂送入下部气道，来替代内源性缺乏的肺表面活性物质。本药的表面活性特性使其在肺内得以均匀分布。并且在肺泡的气液界面展开。本药对于表面活性物质缺乏的生理学和治疗上的效果已经在各种动物实验中得到充分记录证实。在经剖腹产取出后处死的早产胎兔上，气道内滴入本药可以使肺膨胀度显著改善。在经100%氧做机械通气的早产胎兔，与对照动物相比，气道插管内滴入本药可以观察到极其显著的肺潮气量及肺-胸腔顺应性的增加。对早产胎兔维持标化潮气量在10 mL/kg体重的机械通气并给予本药治疗，可以使肺-胸腔系统顺应性改善达到接近成熟胎兔的水平。大规模国际临床试验验证了本药对于呼吸窘迫综合征患儿的治疗效果。早产新生婴儿在给予单剂量(2.5 mL/kg体重，相当于200 mg/kg体重的磷脂)本药治疗后，显示快速和极其显著的改善氧合作用 ：吸入氧浓度(FiO2)减少，PaO2/ FiO2及a/APO2比例的提高，同时亦可不必反复给药。此药减少了呼吸窘迫综合征的病死率和主要肺部并发症的发生。根据临床情况，给予1-2次重复剂量，每次100 mL/kg体重可以进一步减少病死率及呼吸道疾病发生率。

· 【生产厂家】意大利:Chiesi Farmaceutici S.p.A.

· 【生产地址】Via San Leonardo 96-Via Palermo 26/A-Via Ortles 6-43100 Parma

 

Drug Description

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CUROSURF 
(poractant alfa) for Intratracheal Use

DESCRIPTION

CUROSURF (poractant alfa) is a sterile, non-pyrogenic pulmonary surfactant intended for intratracheal use only. CUROSURF is an extract of natural porcine lung surfactant consisting of 99% polar lipids (mainly phospholipids) and 1% hydrophobic low molecular weight proteins (surfactant associated proteins SP-B and SP-C).

CUROSURF is a white to creamy white suspension of poractant alfa. Each milliliter of suspension contains 80 mg of poractant alfa (surfactant extract) that includes 76 mg of phospholipids and 1 mg of protein of which 0.45 mg is SP-B and 0.59 mg is SP-C. The amount of phospholipids is calculated from the content of phosphorus and contains 55 mg of phosphatidylcholine of which 30 mg is dipalmitoylphosphatidylcholine. It is suspended in 0.9% sodium chloride solution. The pH is adjusted with sodium bicarbonate to a pH of 6.2 (5.5 to 6.5).

CUROSURF contains no preservatives.

Indications & Dosage

INDICATIONS

CUROSURF® (poractant alfa) Intratracheal Suspension is indicated for the rescue treatment of Respiratory Distress Syndrome (RDS) in premature infants. CUROSURF reduces mortality and pneumothoraces associated with RDS.

DOSAGE AND ADMINISTRATIONImportant Administration Instructions

For intracheal administration only.

CUROSURF should be administered by, or under the supervision of clinicians experienced in intubation, ventilator management, and general care of premature infants. Before administering CUROSURF, assure proper placement and patency of the endotracheal tube. At the discretion of the clinician, the endotracheal tube may be suctioned before administering CUROSURF. Allow the infant to stabilize before proceeding with dosing.

Administer CUROSURF either:

· Intratracheally by instillation in two divided aliquots through a 5 French end-hole catheter after briefly disconnecting the endotracheal tube from the ventilator; or

· Intratracheally in a single aliquot through the secondary lumen of a dual lumen endotracheal tube without interrupting mechanical ventilation.

Recommended Dosage

The initial recommended dose is 2.5 mL/kg birth weight (see Table 1), administered as one or two aliquots depending upon the instillation procedure [see Preparation of the CUROSURF Suspension].

Up to two repeat doses of 1.25 mL/kg birth weight each may be administered at approximately 12-hour intervals in infants who remain intubated and in whom RDS is considered responsible for their persisting or deteriorating respiratory status. The maximum recommended total dosage (sum of the initial and up to two repeat doses) is 5 mL/kg.

Table 1: CUROSURF Weight-Based Dosing Chart for Rescue Treatment of RDS

Preparation Of The CUROSURF Suspension

1. Remove the vial of CUROSURF suspension from a refrigerator at +2 to +8°C (36 to 46°F) and slowly warm the vial to room temperature before use.

2. Visually inspect the CUROSURF suspension for discoloration prior to administration. The color of the CUROSURF suspension should be white to creamy white. Discard the CUROSURF vial if the suspension is discolored.

3. Gently turn the vial upside-down, in order to obtain a uniform suspension. DO NOT SHAKE.

4. Locate the notch (FLIP UP) on the colored plastic cap and lift the notch and pull upwards.

5. Pull the plastic cap with the aluminum portion downwards.

6. Remove the whole ring by pulling off the aluminum wrapper.

7. Remove the rubber cap to extract content.

8. Unopened, unused vials of CUROSURF suspension that have warmed to room temperature can be returned to refrigerated storage within 24 hours for future use. Do not warm to room temperature and return to refrigerated storage more than once. Protect from light.

AdministrationFor Endotracheal Tube Instillation Using a 5 French End-Hole Catheter

1. Slowly withdraw the entire contents of the vial of CUROSURF suspension into a 3 or 5 mL plastic syringe through a large-gauge needle (e.g., at least 20 gauge). Enter each single-use vial only once.

2. Attach the pre-cut 8-cm 5 end-hole French catheter to the syringe. Fill the catheter with CUROSURF suspension. Discard excess CUROSURF through the catheter so that only the dose to be given remains in the syringe.

3. When administering CUROSURF using a 5 French end-hole catheter, administer in two divided aliquots: • For the first dose: 1.25 mL/kg (birth weight) per aliquot

o For each repeated dose: 0.635 mL/kg (birth weight) per aliquot

4. First aliquot of CUROSURF suspension:

a. Position the infant in a neutral position (head and body in alignment without inclination), with either the right or left side dependent.

a. Immediately before CUROSURF administration, change the infant's ventilator settings to a rate of 40-60 breaths/minute, inspiratory time 0.5 second, and supplemental oxygen sufficient to maintain SaO2 > 92%.

b. Briefly disconnect the endotracheal tube from the ventilator.

c. Insert the pre-cut 5 French catheter into the endotracheal tube and instill the first aliquot of CUROSURF suspension.

d. After the first aliquot is instilled, remove the catheter from the endotracheal tube and manually ventilate the infant with 100% oxygen at a rate of 40-60 breaths/minute for one minute.

1. Second aliquot of CUROSURF suspension:

a. When the infant is stable, reposition the infant such that the other side is dependent.

b. Administer the remaining aliquot using the same procedures as the first aliquot.

2. After completion of the dosing procedure, resume usual ventilator management and clinical care. Do not suction airways for 1 hour after surfactant instillation unless signs of significant airway obstruction occur. Post dosing, consider maintenance of PaO2 of about 55 mmHg, PaCO2 of 35-45, and pH > 7.3 [see Clinical Studies].

For endotracheal instillation using the secondary lumen of a dual lumen endotracheal tube

1. Slowly withdraw the entire contents of the vial of CUROSURF suspension into a 3 or 5 mL plastic syringe through a large-gauge needle (e.g., at least 20 gauge). Do not attach 5 French end-hole catheter. Remove the needle and discard excess CUROSURF so that only the dose to be given remains in the syringe.

2. Keep the infant in a neutral position (head and body in alignment without inclination).

3. Administer CUROSURF suspension through the proximal end of the secondary lumen of the endotracheal tube as a single dose, given over 1 minute, and without interrupting mechanical ventilation.

4. After completion of this dosing procedure, ventilator management may require transient increases in FiO2 , ventilator rate, or PIP. Do not suction airways for 1 hour after surfactant instillation unless signs of significant airway obstruction occur.

HOW SUPPLIEDDosage Forms And Strengths

CUROSURF (poractant alfa) is an intratracheal suspension available in vials:

· 1.5 mL [120 mg poractant alfa (surfactant extract)], or

· 3 mL [(240 mg poractant alfa (surfactant extract)].

CUROSURF is a white to creamy white suspension. Each mL of suspension contains 80 mg poractant alfa (surfactant extract) that includes 76 mg of phospholipids and 1 mg of protein of which 0.45 mg is SP-B and 0.59 mg is SP-C.

Storage And Handling

CUROSURF (poractant alfa) intratracheal suspension is available in sterile, rubber-stoppered clear glass vials containing (one vial per carton):

· 1.5 mL [120 mg poractant alfa (surfactant extract)] of suspension: NDC Number: 10122-510-01

· 3 mL [(240 mg poractant alfa (surfactant extract)] of suspension. NDC Number: 10122-510-03

Store CUROSURF intratracheal suspension in a refrigerator at +2 to +8°C (36 to 46°F). PROTECT FROM LIGHT. Do not shake. Vials are for single use only. After opening the vial discard the unused portion [seePreparation of the CUROSURF Suspension].

Side Effects & Drug Interactions

SIDE EFFECTSClinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adverse Reactions In Studies In Premature Infants With Respiratory Distress Syndrome

The safety data described below reflect exposure to CUROSURF at a single dose of 2.5 mL/kg (200 mg/kg), in 78 infants of 700-2000 grams birth weight with RDS requiring mechanical ventilation and a FiO2 ≥ 0.60 (Study 1) [see Clinical Studies]. A total of 144 infants were studied after RDS developed and before 15 hours of age; 78 infants received CUROSURF 2.5 mL/kg single dose (200 mg/kg), and 66 infants received control treatment (disconnection from the ventilator and manual ventilation for 2 minutes).

Transient adverse effects seen with the administration of CUROSURF included bradycardia, hypotension, endotracheal tube blockage, and oxygen desaturation. The rates of the most common serious complications associated with prematurity and RDS observed in Study 1 are shown in Table 2.

Table 2: Most Common Serious Complications Associated with Prematurity and RDS in Study 1

Seventy-six infants (45 treated with CUROSURF) from study 1 were evaluated at 1 year of age and 73 infants (44 treated with CUROSURF) were evaluated at 2 years of age to assess for potential long-term adverse reactions. Data from follow-up evaluations for weight and length, persistent respiratory symptoms, incidence of cerebral palsy, visual impairment, or auditory impairment was similar between treatment groups. In 16 patients (10 treated with CUROSURF and 6 controls) evaluated at 5.5 years of age, the developmental quotient, derived using the Griffiths Mental Developmental Scales, was similar between groups.

Immunogenicity

Immunological studies have not demonstrated differences in levels of surfactant-anti-surfactant immune complexes and anti-CUROSURF antibodies between patients treated with CUROSURF and patients who received control treatment.

Postmarketing Experience

Pulmonary hemorrhage, a known complication of premature birth and very low birth-weight, has been reported both in clinical trials with CUROSURF and in postmarketing adverse event reports in infants who had received CUROSURF.

DRUG INTERACTIONS

No information provided.

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONSAcute Changes In Oxygenation And Lung Compliance

The administration of exogenous surfactants, including CUROSURF, can rapidly affect oxygenation and lung compliance. Therefore, infants receiving CUROSURF should receive frequent clinical and laboratory assessments so that oxygen and ventilatory support can be modified to respond to respiratory changes. CUROSURF should only be administered by those trained and experienced in the care, resuscitation, and stabilization of pre-term infants.

Administration-Related Adverse Reactions

Transient adverse reactions associated with administration of CUROSURF include bradycardia, hypotension, endotracheal tube blockage, and oxygen desaturation. These events require stopping CUROSURF administration and taking appropriate measures to alleviate the condition. After the patient is stable, dosing may proceed with appropriate monitoring.

Nonclinical ToxicologyCarcinogenesis, Mutagenesis, Impairment Of Fertility

Studies to assess potential carcinogenic effects of CUROSURF have not been conducted.

Poractant alfa was negative for genotoxicity in the following assays: bacterial reverse mutation assay (Ames test), gene mutation assay in Chinese hamster V79 cells, chromosomal aberration assay in Chinese hamster ovary cells, unscheduled DNA synthesis in HELA S3 cells, and in vivo mouse micronucleus assay.

No studies to assess reproductive effects of CUROSURF have been performed.

Use In Specific PopulationsPediatric Use

CUROSURF is indicated for the rescue treatment, including the reduction of mortality and pneumothoraces, of Respiratory Distress Syndrome (RDS) in premature infants [see INDICATIONS AND USAGE and DOSAGE ADMINISTRATION].

The safety and efficacy of CUROSURF in the treatment of full term infants or older pediatric patients with respiratory failure has not been established.

Overdosage & Contraindications

OVERDOSE

There have been no reports of overdosage following the administration of CUROSURF.

In the event of accidental overdosage, and if there are clear clinical effects on the infant's respiration, ventilation, or oxygenation, aspirate as much of the suspension as possible and provide the infant with supportive treatment, with particular attention to fluid and electrolyte balance.

CONTRAINDICATIONS

None.

Clinical Pharmacology

CLINICAL PHARMACOLOGYMechanism Of Action

Endogenous pulmonary surfactant reduces surface tension at the air-liquid interface of the alveoliduring ventilation and stabilizes the alveoli against collapse at resting transpulmonary pressures. A deficiency of pulmonary surfactant in preterm infants results in Respiratory Distress Syndrome (RDS) characterized by poor lung expansion, inadequate gas exchange, and a gradual collapse of the lungs(atelectasis).

CUROSURF compensates for the deficiency of surfactant and restores surface activity to the lungs of these infants.

Pharmacodynamics

In vitro - CUROSURF lowers minimum surface tension to ≤ 4mN/m as measured by the Wilhelmy Balance System.

Pharmacokinetics

CUROSURF is administered directly to the lung, where biophysical effects occur at the alveolar surface. No human pharmacokinetic studies have been performed to characterize the absorption, biotransformation, or elimination of CUROSURF.

Clinical StudiesRescue Treatment Of Respiratory Distress Syndrome

The clinical efficacy of CUROSURF in the treatment of established Respiratory Distress Syndrome (RDS) in premature infants was demonstrated in one single-dose study (Study 1) and one multiple-dose study (Study 2) involving approximately 500 infants. Each study was randomized, multicenter, and controlled.

In study 1, premature infants 700 to 2000 grams birth weight with RDS requiring mechanical ventilationand a FiO2 ≥ 0.60 were enrolled. CUROSURF 2.5 mL/kg single dose (200 mg/kg) or control (disconnection from the ventilator and manual ventilation for 2 minutes) was administered after RDS developed and before 15 hours of age. The results from Study 1 are shown below in Table 3.

Table 3: Study 1 Results in Premature Infants with Respiratory Distress Syndrome

In Study 2, premature infants 700 to 2000 g birth weight with RDS requiring mechanical ventilation and a FiO2 ≥ 0.60 were enrolled. In this two-arm trial, CUROSURF was administered after RDS developed and before 15 hours of age, as a single-dose or as multiple doses. In the single-dose arm, infants received CUROSURF 2.5 mL/kg (200 mg/kg). In the multiple-dose arm, the initial dose of CUROSURF was 2.5 mL/kg followed by up to two 1.25 mL/kg (100 mg/kg) doses of CUROSURF. The results from Study 2 are shown below in Table 4.

Table 4: Study 2 Results in Premature Infants with Respiratory Distress Syndrome

There is no controlled experience on the effects of administering initial doses of CUROSURF other than 2.5 mL/kg (200 mg/kg), subsequent doses other than 1.25 mL/kg (100 mg/kg), administration of more than three total doses, dosing more frequently than every 12 hours, or initiating therapy with CUROSURF more than 15 hours after diagnosing RDS. Adequate data are not available on the use of CUROSURF in conjunction with experimental therapies of RDS, e.g., high-frequency ventilation or extracorporeal membrane oxygenation.