Exosurf (Colfosceril Palmitate)


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.

EXOSURF® NEONATAL Glaxo Wellcome Colfosceril Palmitate Synthetic Lung Surfactant

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