Neosurf Product Monograph

SUMMARY PRODUCT INFORMATION

DESCRIPTION

NEOSURF (bovine lipid extract surfactant) is extracted from bovine lung surfactant. The manufacturing process removes hydrophilic proteins, the majority of which would be surfactant-associated protein SP-A, and selects for hydrophobic phospholipids and surfactant-associated proteins SP-B and SP-C.

INDICATIONS AND CLINICAL USE

• NEOSURF (bovine lipid extract surfactant) is indicated for rescue treatment of Neonatal

  Respiratory Distress Syndrome (NRDS/Hyaline Membrane Disease).

For infants with NRDS confirmed by x-ray and who require mechanical ventilation, with arterial to alveolar oxygen ratio (PaO2/PAO2) <0.22, NEOSURF is to be given as soon as possible after the oxygenation criteria are met.

The use of NEOSURF in infants less than 380 g or greater than 4460 g birth weight has not been evaluated in controlled trials.

CONTRAINDICATIONS

Use of NEOSURF (bovine lipid extract surfactant) is contraindicated in infants with active pulmonary haemorrhage.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

• Administer in a highly supervised clinical setting.
• NEOSURF can affect oxygenation and lung compliance rapidly. In some infants, hyperoxia may occur within minutes of administration.
• Transient episodes of bradycardia and decreased oxygen saturation may occur during dosing.

General

NEOSURF (bovine lipid extract surfactant) is intended for intratracheal use only (See DOSAGE AND ADMINISTRATION).

Use of NEOSURF should be restricted to a highly supervised clinical setting with immediate availability of experienced neonatologists and other clinicians experienced with intubation, ventilator management, and general care of premature infants.

A higher rate of sepsis has been described in those infants treated with NEOSURF than those in the control arm. Health professionals caring for these infants should be aware of this increased risk, take appropriate precautionary measures and be vigilant for any signs and symptoms of sepsis.

Carcinogenesis and Mutagenesis

No studies have been performed to investigate the carcinogenesis or mutagenesis of NEOSURF.

Immunogenicity

Long-term studies comparing NEOSURF to placebo (sham air) treatment demonstrated no significant differences in development of allergic manifestations.

Ophthalmologic

Hyperoxia may occur within minutes of administration of NEOSURF. If hyperoxia develops and oxygen saturation is in excess of 95%, Fi_O2 should be reduced until saturation is 90 to 95%, to decrease the risk of retinopathy of prematurity.

Respiratory

Vigilant clinical attention should be given to all infants prior to, during and after administration of NEOSURF. Infants receiving NEOSURF should be monitored for oxygenation with a transcutaneous oxygen probe or oxygen saturation monitor as well as occasional blood gas measurements. In addition, carbon dioxide (CO₂) levels should be monitored with transcutaneous CO₂ probe correlated with blood gas readings.

NEOSURF can rapidly affect oxygenation and lung compliance. If the improvement in chest expansion seems excessive, peak ventilator inspiratory pressures should be reduced immediately, to avoid overdistension and pulmonary air leaks. Monitor tidal volume after dosing, as sudden

lung compliance may occur without much chest movement.

During the dosing procedure, transient episodes of bradycardia and decreased oxygen saturation have been reported (See ADVERSE REACTIONS). If these occur, the dosing procedure should be stopped and appropriate measures to alleviate the condition initiated. After stabilization, the dosing procedure can be resumed.

Administration techniques used with other surfactant products, such as slow administration or the use of small test aliquots, are not recommended with NEOSURF. Unlike other products that require a slow drip to prevent reflux, NEOSURF has a much lower viscosity and a higher protein content that promote a more rapid distribution. Slow administration may lead to uneven distribution, resulting in uneven lung compliance.

If the dose fails to subside in the ETT with additional pressures recommended in the DOSAGE AND ADMINISTRATION section, consider the possibility of a mucous plug.

Mucous Plugs: Infants whose ventilation becomes markedly impaired during or shortly after dosing may have mucous 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. After dosing, exogenous surfactant may encourage the transport of resident mucus. 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.

Monitoring and Laboratory Tests

Correction of acidosis, hypotension, hypoglycemia and hypothermia is recommended prior to administration.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Very common adverse events occurring in ≥ 10% of infants who received NEOSURF (bovine lipid extract surfactant), in descending order of frequency, were patent ductus arteriosus, decreased post-dose pulmonary function values, intraventricular haemorrhage of all grades, sepsis, retinopathy of prematurity, bradycardia and severe intraventricular haemorrhage.

Common adverse events occurring in ≥ 1% and < 10% of infants who received NEOSURF, in descending order of frequency, were pulmonary interstitial emphysema, periventricular leukomalacia, pneumothorax, pulmonary haemorrhage, endotracheal tube complications, necrotizing enterocolitis, respiratory acidosis, convulsions, hypotension, apnoea, hydrocephalus and pneumonia.

Due to the rapid effect of NEOSURF on lung compliance and oxygenation, infants should be monitored for respiratory parameters and any of the common adverse events.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information

from clinical trials is useful for identifying drug-related adverse events and approximating rates.

In a double-blinded, comparative, multicentre clinical trial comparing the safety and efficacy of NEOSURF and Exosurf^® Neonatal (colfosceril palmitate; Glaxo Wellcome), 568 infants received NEOSURF and 565 received Exosurf^® for rescue treatment of NRDS.

Adverse events occurring in ≥ 1% of infants treated with NEOSURF are summarized by body system and in order of decreasing frequency in Table 1, below. The incidence of these events in Exosurf^®-treated infants is provided for comparison.

* Almost all incidences of respiratory acidosis occurred at one study site.

** The term “decreased pulmonary function” covered incidences of a fall in saturation or oxygenation, or an increase in CO₂ values after dosing.

The most frequent events reported to occur in either treatment group were patent ductus arteriosus in almost half of the infants, and decreased pulmonary function (defined as incidences of a fall in saturation or oxygenation, or an increase in CO₂ values after dosing) in approximately one third of infants. These events occurred with similar frequency in either treatment group, and are anticipated complications when infants in distress are handled.

Sepsis and pneumonia occurred significantly more frequently in NEOSURF -treated infants than in those who received Exosurf^®. Notwithstanding this higher incidence of sepsis, death due to infections was comparable between the two arms of the study.

Although the incidence of pulmonary haemorrhage was low (<1%) within the first two hours after dosing, it was observed to increase to 8% before discharge from intensive care. This was not significantly different from the incidence of pulmonary haemorrhage with Exosurf^®. For the 750 - 1250 gram birth weight group receiving NEOSURF, 7 of 32 deaths (22%) were attributed to pulmonary haemorrhage.

There was a significantly greater incidence of respiratory acidosis following treatment with NEOSURF. All incidences of respiratory acidosis occurred within two hours of dosing, and almost all incidences following either surfactant occurred at one study centre, perhaps due to too rapid weaning of the ventilatory pressure and rate with decreased minute ventilation.

Significantly fewer infants who received NEOSURF developed pulmonary interstitial emphysema or pneumothorax than did those who were treated with Exosurf^®. This may reflect the increased ventilatory requirements of infants who received Exosurf^®. Thus, a reduction in ventilatory pressure following treatment with NEOSURF may protect infants from pulmonary air leaks.

Table 2, below, summarizes the adverse events that were reported to occur within two hours post-dose, in ≥ 1% of infants treated with NEOSURF. The incidence of these events in Exosurf^®

-treated infants is provided for comparison.

* Almost all incidences of respiratory acidosis occurred at one study site.

** The term “decreased pulmonary function” covered incidences of a fall in saturation or oxygenation, or an increase in CO₂ values.

Decreased pulmonary function (reported incidences of a fall in saturation or oxygenation, or an increase in CO₂ values), bradycardia and endotracheal tube complications occurred with the same frequency in each treatment group, and are commonly associated with handling and treatment of premature infants. As discussed above, respiratory acidosis occurred, for the most part, at one site and may have been due to inadequate monitoring of lung compliance at that site.

Other adverse events that were reported to occur within two hours after administration of NEOSURF, but at a frequency of <1% were: acidosis; hypertension; hypotension; hypoxia;

patent ductus arteriosus; pneumonia; pneumothorax; and pulmonary haemorrhage.

Less Common Clinical Trial Adverse Drug Reactions

Uncommon adverse events that were reported to occur in < 1% of infants treated with NEOSURF were:

Infections and infestations: miscellaneous infections other than pneumonia.

Blood and lymphatic system: neonatal coagulation disorder, neonatal jaundice; thrombocytopenia.

Endocrine disorders: hypercalcaemia; hypoglycaemia.

Metabolism and nutritional: acidosis; hyperkalemia.

Nervous system disorders: abnormal electroencephalogram; cerebral infarction; encephalopathy; ependymitis; meningitis.

Cardiac disorders: cardiac arrest; cardiomegaly; cor pulmonale; hypertrophic cardiomyopathy; pneumopericardium; pulmonary oedema; pulmonary valve stenosis; supraventricular tachycardia.

Vascular disorders: haemorrhage; hypertension.

Respiratory disorders: asphyxia; bronchopulmonary dysplasia; hypoxia; pulmonary hypertension.

Gastrointestinal disorders: enteritis; gastrointestinal haemorrhage; gastrointestinal reflux; ileus; intestinal perforation; pneumoperitoneum.

Hepato-biliary disorders: hepatomegaly.

Skin disorders: cellulitis.

Renal and urinary disorders: anuria; hydronephrosis; hydroureter; nephrocalcinosis.

General disorders: growth retardation; neonatal hypothermia.

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory values were not collected in clinical trials. However, respiratory acidosis was reported as an adverse event in 4% of infants receiving NEOSURF and 2% of those receiving Exosurf^® (p<0.05). Respiratory acidosis occurred primarily at one study centre. Lung compliance and oxygenation should be monitored closely, as ventilation parameters may change rapidly after dosing (See WARNINGS AND PRECAUTIONS).

Post-Market Adverse Drug Reactions

No new adverse reactions have been reported, nor has there been an increase in the incidence of known adverse reactions identified in the clinical trials.

Three infants at one site, who were administered very small aliquots of 1 mL at a time without rotation of the infant, developed pulmonary haemorrhage, intraventricular haemorrhage and/or periventricular leukomalacia, and died. The very small doses given without rotation may have led to uneven surfactant distribution and uneven lung compliance.

DRUG INTERACTIONS

There are no known drug interactions between NEOSURF and other substances. NEOSURF is not known to interfere with laboratory results.

Clinical experience with NEOSURF has shown it to be safe and effective when used with nitric oxide therapy, high frequency oscillation and extracorporeal membranous oxygenation.

DOSAGE AND ADMINISTRATION

Dosing Considerations

NEOSURF (bovine lipid extract surfactant) is intended for intratracheal instillation only after an endotracheal airway has been established.

NEOSURF does not require reconstitution or filtering before use. Vials are for single use only, to ensure sterility. Once at room temperature, gently swirl or invert the vial to suspend the lipid and disperse any agglomerates. Inspect the vial for homogeneity. It is normal for warmed vials to have an even dispersion of fine but visible flecks of lipid. Contents should appear as an off-white to light yellow suspension. If contents are a darker colour or will not disperse evenly, discard the vial. Report this and the lot number to the manufacturer.

NEOSURF should be warmed to at least room temperature, but no higher than body temperature before being administered. Warming can be accomplished in the following ways (times are approximate):

Method of Warming Refrigerated Vials Frozen Vials In the hand 5 min. 10 to 15 min. On the counter 20 min. 60 min. In a 37°C water bath 2 min. 5 min.

Recommended Dosage

The recommended dosage of NEOSURF is 5 mL/kg at 27 mg of phospholipids/mL, which equals 135 mg phospholipid/kg. As many as 3 subsequent doses of NEOSURF can be given within the first 5 days of life. See Repeat Doses for details. Table 3 suggests the total dosage for a range of birth weights.

Administration

Dosing Procedures

The infant should be suctioned and allowed to recover before commencing the procedure. Ensure proper placement of the endotracheal tube (ETT) via chest auscultation and radiograph, if available (1-2 cm below the vocal cords, 1-2 cm above the carina). Do not instill NEOSURF down the right mainstem bronchus.

Draw the full dose into a syringe with a large gauge needle, and fit the needle with a sterile #5 Fr feeding tube which has been cut to an appropriate length so that it will reach the distal tip of the ETT. Discharge the syringe to fill the feeding tube with surfactant. Briefly disconnect the infant from the ventilator so that the feeding tube may be threaded into the ETT. Alternately, to allow simultaneous mechanical ventilation or hand bagging, pass the feeding tube through the suction valve of a closed suctioning adaptor attached to the ETT.

Instill as a single bolus dose or up to three aliquots, as tolerated, with the infant supine for the first aliquot, then rotated to the left and right for subsequent aliquots. Instill each aliquot or dose over 2 to 3 seconds. After each aliquot is instilled, the infant should be ventilated manually for 30 seconds, using pressures sufficient to achieve good chest expansion before returning the infant to the ventilator. If the infant remains on mechanical ventilation during dosing, raise the pressure by 1 to 2 cm H₂O, if necessary, to assist with emptying the ETT. Allow approximately 1-2 minutes recovery time after each aliquot. Ensure oxygen saturation readings are about 95% before commencing the next aliquot.

The volume of surfactant will rise in the ETT during administration. If the surfactant is slow to subside, interrupt administration and hand ventilate until the ETT is clear before continuing. If

the surfactant fails to subside, investigate the possibility of a mucous plug. Small aliquots or a slow drip are not recommended, as this may lead to poor surfactant distribution and uneven lung compliance.

Monitoring after administration

Once instillation is complete, new mechanical ventilatory parameters need to be established according to the TcP_O2/TcP_CO2 readings, the oxygen saturation monitor and chest expansion. TcP_O2/TcP_CO2 readings are preferred in infants of lower gestation (less than 32 weeks), and oxygen saturation readings preferred with older infants. Monitor tidal volume closely, as sudden lung compliance may occur without much chest movement. Start at pre-instillation settings and wean the pressures (PIP/PEEP), Fi_O2 and the ventilator rate, as indicated by the infant’s status. Follow-up blood gases one hour after dosing is a standard procedure for any infant who has received NEOSURF (Pa_O2 should be between 60-70 torr, Pa_CO2 should be kept between 35-45 torr, and pH between 7.35 - 7.45). Avoid suctioning for 2 hours post-NEOSURF, unless absolutely necessary. Due to the immediate effect of NEOSURF on lung compliance and oxygenation (usually within 5 to 30 minutes), Fi_O2 should be decreased accordingly, to prevent hyperoxia. Chest expansion should be observed closely and ventilatory pressures (PIP/PEEP) decreased accordingly. High oxygen saturation levels (>95%) or high TcP_O2/TcP_CO2 readings (as confirmed by comparison to blood gas measurements) indicate the infant should be weaned off Fi_O2, ventilator rates and pressures. Blood gas readings should be 60 - 70 torr for Pa_O2 and 35 - 45 torr for Pa_CO2. Failure to wean appropriately may result in a pneumothorax.

Infants whose ventilation becomes markedly impaired during or shortly after dosing may have mucous plugging of the ETT, particularly if pulmonary secretions were prominent prior to drug administration. In addition, surfactant may promote the movement of resident mucus. If suctioning is unsuccessful in removing the obstruction, the blocked ETT should be replaced immediately.

Repeat Doses

Neonates can receive up to 3 additional doses of NEOSURF within the first 5 days of life. The criteria for an additional dose are a positive response to the previous dose, and an increase in respiratory support as signalled by a gradual increase in Fi_O2. This increase must be at least 10% greater than the Fi_O2 required after the initial response to the previous dose of NEOSURF.

All infants exhibiting respiratory deterioration should be evaluated for a patent ductus arteriosus (PDA), pneumothorax and pulmonary haemorrhage before retreatment with NEOSURF. The regimen for repeat doses is the same as for the initial dose. See Dosing Procedures for details.

OVERDOSAGE

No evidence of human overdose with NEOSURF (bovine lipid extract surfactant) has been documented. Based on animal data, overdosage may result in acute airway obstruction.

ACTION AND CLINICAL PHARMACOLOGY

NEOSURF (bovine lipid extract surfactant) restores surfactant activity in neonates with respiratory distress syndrome (NRDS), thereby improving gaseous exchange by decreasing alveolar surface tension and promoting lung compliance in the infant with NRDS.

NEOSURF is an extract of natural bovine surfactant which contains numerous phospholipids, with dipalmitoylphosphatidylcholine (DPPC) being the most abundant. It also includes hydrophobic surfactant-associated proteins SP-B and SP-C, which facilitate their dispersion. When administered intratracheally, NEOSURF is rapidly adsorbed, forming an active phospholipid monolayer at the air-fluid interface.

The metabolic fate of NEOSURF has not been investigated.

NEOSURF can have an immediate effect on lung compliance, usually within 5 to 30 minutes after treatment with a single dose. Clinical experience with NEOSURF has shown that NEOSURF significantly improved gas exchange and lung compliance by the 4-hour time-point. Fraction of inspired oxygen (Fi_O2) and ventilatory requirements were significantly decreased, and there was a reduction in the severity of NRDS and its associated complications.

STORAGE AND STABILITY

NEOSURF (bovine lipid extract surfactant) has a shelf life of 36 months when stored frozen below -10°C. Do not use past expiry date on label. Store vials in cartons until ready for use. Frozen product may have two excursions to 2°–8°C for a combined maximum of two weeks.

Alternately, NEOSURF may be stored refrigerated (2°– 8ºC) upon receipt, for up to 10 months. In the space provided on the vial labelling, record the new expiry date of up to 10 months from the day it is received. Refrigerated vials should not be returned to the freezer.

An unopened vial warmed to room temperature for less than 6 hours, may be returned to its previous storage condition a maximum of 2 times. In the space provided on the vial labelling, record the number of times the vial has been warmed and returned to storage.

SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions.

DOSAGE FORMS, COMPOSITION AND PACKAGING

NEOSURF (bovine lipid extract surfactant) is a suspension for intratracheal instillation.

Each mL of NEOSURF contains 27 mg of phospholipids and 176 – 500 µg of surfactant-associated proteins SP-B and SP-C, with 0.10 M sodium chloride and 0.0015 M calcium chloride. NEOSURF contains no preservatives.

NEOSURF is available in 3 mL, 4 mL, and 5 mL sterile, single use clear glass vials, packaged individually or in cartons of 10 vials.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Bovine lipid extract surfactant is an extract of bovine pulmonary surfactant that contains numerous phospholipids and hydrophobic surfactant associated proteins SP-B and SP-C.

The phospholipids are present in the following ratio, expressed as a percent of the total phospholipid concentration.

Phospholipid Concentration (mol%) Phosphatidylcholine

Phosphatidylglycerol

Phosphatidylethanolamine

Phosphatidylinositol

Phosphatidylserine

Sphingomyelin

Lyso-phosphatidylcholine

Lyso-bis-phosphatidic acid

75 - 85 12 - 17 1 - 5

0 - 2

0 - 2

0 - 5

0 - 2.5 0 - 2.4

The hydrophobic proteins are surfactant-associated proteins SP-B and SP-C present at 6.5 - 18.5 µg/mg phospholipid.

Product Characteristics

Phospholipids and hydrophobic proteins SP-B and SP-C are isolated from bovine lung surfactant, then suspended in a sodium chloride and calcium chloride solution, which is heat sterilized in single-use vials.

CLINICAL TRIALS

Study demographics and trial design

The efficacy of NEOSURF (bovine lipid extract surfactant) is supported by the results of a Phase III pivotal trial, Study No. 92-001, comparing the safety and efficacy of NEOSURF with Exosurf^® Neonatal (colfosceril palmitate; Glaxo Wellcome) in the rescue treatment of neonates with respiratory distress syndrome. Exosurf^® was chosen as the comparator because it was the only approved exogenous surfactant therapy available in Canada at that time.

This 10 centre double-blinded randomized controlled trial involved 1133 infants. Infants were stratified into weight groups of <750 grams (n=180), 750-1250 grams (n=455) and >1250 grams (n=499). Infants could receive up to four doses of surfactant, as required, within the first five days of life.

Infants with NRDS were enrolled in three birth weight arms and randomized to receive NEOSURF or Exosurf^®. There were no statistically significant differences between treatment groups for demographic variables or pre-dose complications, except a significantly greater incidence of prolonged rupture of the membranes (PROM) in NEOSURF-treated infants weighing 750-1250 g compared with those receiving Exosurf^® (26% and 18%, respectively; p=0.0450). Because both treatment groups had a similar severity of hyaline membrane disease prior to treatment, as measured by ventilation parameters, age of intubation and age of first treatment, this increased incidence of PROM was considered not likely to have affected the study outcomes.

Study results

Efficacy parameters were evaluated by birth weight group. Table 5 provides results for intact cardiopulmonary survival and ventilatory requirements.

NEOSURF was as effective as the comparator Exosurf^® for intact cardiopulmonary survival at 36 weeks gestational age. NEOSURF was as effective or more effective than Exosurf^® for secondary endpoints. Of infants treated in the 750-1250 g arm:

• significantly more infants treated with NEOSURF were alive at discharge (p=0.0435);
• infants treated with NEOSURF had fewer air leaks (p<0.0001);

• infants treated with NEOSURF had a decreased incidence of high oxygen requirements

  (p=0.0234); and

• there were no significant differences in the incidences of IVH (intraventricular haemorrhage) or severe IVH/PVL (periventricular leukomalacia).

Other Studies

A published study by Lam et al. (2005) compared the efficacy of NEOSURF and Survanta^® in a randomized clinical trial in premature infants with birth weights between 500 and 1,800 g who developed RDS requiring mechanical ventilation with oxygen requirements of more than 3% within the first 6 hours of life. Sixty infants were recruited, with 29 in the NEOSURF and 31 in the Survanta^® group. The trial was not blinded due to the different administration methods recommended for each product, particularly the number of aliquots and rotations. The primary outcome was the oxygen index within 12 hr of treatment. Neonatal complications were analyzed as secondary outcomes.

Both groups had significant and sustained improvements in their oxygenation index after treatment, with the NEOSURF group associated with a significantly lower oxygenation index throughout the 12-hr period compared with infants who received Survanta^®. There was no difference in secondary outcomes, including mortality, ventilator days and occurrence of chronic lung disease. The authors attributed the difference in speed of response to the higher concentration of surfactant-associated proteins in NEOSURF.

In open-label trials, over 5000 infants have received NEOSURF.

Long-term studies comparing NEOSURF to placebo (sham air) treatment demonstrated no significant differences in development of neurodevelopmental handicaps and allergic manifestations.

DETAILED PHARMACOLOGY

Twenty adult sheep were given a non-uniform pattern of lung injury by repetitive saline lavage followed by HCl instillation, until arterial P_O2 fell below 90 Torr. After the final lavage, the sheep were mechanically ventilated for 60 min before treatment with either NEOSURF (bovine lipid extract surfactant) or Survanta^® (beractant, Abbott) which had been radiolabelled. Ten animals received 10 mL of surfactant by nebulizer, with 5 mL aliquots added as needed over a three-hour treatment period. Ten animals received instilled surfactant at a dose of 100 mg phospholipid/kg body weight, applied in three aliquots over several inspiratory breaths, while being turned.

The sheep given instilled NEOSURF, aerosolized Survanta^® and instilled Survanta^® had significantly increased Pa_O2 values and decreased A-aP_O2 values by 180 min compared with their respective pretreatment values (p<0.01). Those given aerosolized NEOSURF had no statistically significant changes in either Pa_O2 or A-aP_O2 values over this treatment period. Animals given instilled NEOSURF had significantly higher Pa_O2 and lower A-aP_O2 values than did the other three groups at each time point after treatment (p<0.01). Aerosolized NEOSURF values at 180 min were significantly inferior to the other treatment groups (p<0.05).

Pa_CO2 values following instillation of NEOSURF were significantly lower than the pretreatment values from 60 min after treatment (p<0.05) through to 180 min (p<0.01). Pa_CO2 values for aerosolized Survanta^® were significantly lower than the pretreatment values (p<0.01), whereas Pa_CO2 values were significantly higher following instilled Survanta^®, and did not change significantly over time for the aerosolized NEOSURF. Animals given instilled NEOSURF or aerosolized Survanta^® had significantly lower Pa_CO2 values than did the animals given either

instilled Survanta^® or aerosolized NEOSURF at any time point after treatment (p<0.05).

Three hours after treatment, the proportion of the recovered surfactant present in the airways relative to lung tissue was greater for animals treated with NEOSURF than those treated with Survanta^® (p<0.05).

Total phospholipid recovery was significantly higher in lavage isolated from the instilled groups compared with the aerosolized groups. The total quantity of protein present in the alveolar lavage was similar for all four treatment groups. The mean small aggregate/large aggregate (SA/LA) of animals given instilled NEOSURF was significantly lower than that of animals receiving instilled Survanta^® (p<0.05). Animals treated with aerosolized NEOSURF had a significantly higher SA/LA than did aerosolized Survanta^® animals (p<0.05).

In conclusion, instilled NEOSURF resulted in the greatest improvement in lung function. Viscosity measurements of each preparation using an Ostwald viscometer, showed Survanta^® to have a viscosity eight times that of NEOSURF. It also was noted that NEOSURF contains significantly more surfactant-associated proteins than does Survanta^®. These factors may have influenced the distribution of each surfactant, as it was observed that there was acute deterioration in ventilatory parameters after instillation of Survanta^®.

TOXICOLOGY

Acute Toxicity

No acute toxicity studies have been conducted with NEOSURF (bovine lipid extract surfactant).

Long-Term Toxicity

In a 17-day intratracheal toxicity study, four groups of male and female western cross lambs were administered NEOSURF or vehicle control by intratracheal instillation every other day for a total of 5 doses. Another four males and four females received no treatment.

Dyspnea was commonly observed during dosing with both the vehicle control and NEOSURF. Two animals given NEOSURF died during the second dosing (Study Day 3) from apparent volume overload (drowning). Further doses of NEOSURF were administered in aliquots spread over several hours. No other consistent adverse pharmacologic, toxicologic or behavioural clinical signs were noted from treatment with NEOSURF or vehicle control.

A localized 2 cm mass (abscess) was observed near the trachea of one lamb in the NEOSURF group; no definitive relationship to treatment was established.

In summary, intratracheal administration of 270 mg/kg NEOSURF in a volume of 10 mL/kg once every other day for a total of 5 doses beginning 24-48 hr after birth produced no distinct or definitive signs of systemic toxicity.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No studies have been performed to investigate the carcinogenesis, mutagenesis or impairment to fertility of NEOSURF.

Immunogenicity

Animal studies for assessing immunogenicity have not been performed.

REFERENCES

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   Dunn MS, Shennan AT, Possmayer F. Single - versus multiple-dose surfactant replacement therapy in neonates of 30 to 36 weeks’ gestation with respiratory distress syndrome. Pediatrics 1990;86:564-

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3. 3. Dunn MS, Shennan AT, Zayack D, Possmayer F. Bovine surfactant replacement therapy in neonates of less than 30 weeks’ gestation: a randomized controlled trial of prophylaxis versus treatment. Pediatrics 1991;87:377-86.
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9. 9.

   Lam BCC, Ng YK, Wong KY. Randomized trial comparing two natural surfactants (Survanta vs.

   bLES) for treatment of neonatal respiratory distress syndrome. Pediatr Pulmonol 2005;39:64-9.

10. 10. Lewis JF, Goffin J, Yue P, McCaig LA, Bjarneson D, Veldhuizen RAW. Evaluation of exogenous surfactant treatment strategies in an adult model of acute lung injury. J Appl Physiol 1996;80: 1156-64.
11. 11. Maeta H, Vidyasagar D, Raju TNK, Bhat R, Matsuda H. Early and late surfactant treatments in baboon model of hyaline membrane disease. Pediatrics 1998;81:277-83.
12. 12. Peliowski A, Finer N.N. A randomized, blinded, Canadian multicenter trial to compare a bovine surfactant (bLES^®) (b), with a synthetic, Exosurf^® (E), for the rescue treatment of respiratory distress syndrome (RDS) in premature newborns ≤ 1250 g. Pediatr Res 1998;43:293A. [Abstract]
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    Possmayer F. Biophysical activities of pulmonary surfactant. In: Polin RA, Fox WW, eds. Fetal and

    Neonatal Physiology. Philadelphia: W.B. Saunders Co., 1991:949-62.

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    Walther, FJ, Taeusch HW. New approaches to surfactant therapy. Neonat Resp Dis 1991;

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