Endogenous lung surfactant is essential for effective ventilation because it modifies alveolar surface tension thereby stabilizing the
alveoli. Lung surfactant deficiency is the cause of Respiratory Distress
Syndrome (RDS) in premature infants. Infasurf restores surface activity to the
lungs of these infants.
Activity
Infasurf adsorbs rapidly to the surface of the air:liquid
interface and modifies surface tension similarly to natural lung surfactant. A minimum
surface tension of ≤ 3 mN/m is produced in vitro by Infasurf as measured
on a pulsating bubble surfactometer. Ex vivo, Infasurf restores the pressure
volume mechanics and compliance of surfactant-deficient rat lungs. In vivo,
Infasurf improves lung compliance, respiratory gas exchange, and survival in
preterm lambs with profound surfactant deficiency.
Animal Metabolism
Infasurf is administered directly to the lung lumen surface,
its site of action. No human studies of absorption, biotransformation, or
excretion of Infasurf have been performed. The administration of Infasurf with
radiolabeled phospholipids into the lungs of adult rabbits results in the
persistence of 50% of radioactivity in the lung alveolar lining and 25% of
radioactivity in the lung tissue 24 hours later. Less than 5% of the
radioactivity is found in other organs. In premature lambs with lethal
surfactant deficiency, less than 30% of instilled Infasurf is present in the
lung lining after 24 hours.
Clinical Studies
The efficacy of Infasurf was demonstrated in two
multiple-dose controlled clinical trials involving approximately 2,000 infants
treated with Infasurf (approximately 100 mg phospholipid/kg) or Exosurf
Neonatal®. In addition, two controlled trials of Infasurf versus Survanta®, and
four uncontrolled trials were conducted that involved approximately 15,500
patients treated with Infasurf.
Infasurf versus Exosurf Neonatal®
Treatment Trial
A total of 1,126 infants ≤ 72 hours of age with RDS who
required endotracheal intubation and had an a/A PO2 < 0.22 were enrolled
into a multiple-dose, randomized, double-blind treatment trial comparing
Infasurf (3mL/kg) and Exosurf Neonatal® (5mL/kg). Patients were given an
initial dose and one repeat dose 12 hours later if intubation was still required.
The dose was instilled in two aliquots through a side port adapter into the
proximal end of the endotracheal tube. Each aliquot was given in small bursts
over 20-30 inspiratory cycles. After each aliquot was instilled, the infant was
positioned with either the right or the left side dependent. Results for
efficacy parameters evaluated at 28 days or to discharge for all treated
patients from this treatment trial are shown in Table 1.
Table 1 - Infasurf vs Exosurf Neonatal® Treatment Trial
| EfficacyParameter |
Infasurf
(N=570)
% |
Exosurf
Neonatal®
(N=556)
% |
p-Value |
| Incidence of air leaks a |
11 |
22 |
≤ 0.001 |
| Death due to RDS |
4 |
4 |
0.95 |
| Any death to 28 days |
8 |
10 |
0.21 |
| Any death before discharge |
9 |
12 |
0.07 |
| BPD b |
5 |
6 |
0.41 |
| Crossover to other surfactantc |
4 |
4 |
1 |
aPneumothorax and/or pulmonary interstitial emphysema.
b BPD is bronchopulmonary dysplasia, diagnosed by positive X-ray and oxygen dependence at 28 days.
c Protocol permitted use of comparator surfactant in patients who failed to respond to therapy with the initial randomized surfactant if the infant was < 96 hours of age, had received a full course of the randomized surfactant, and had an a/A PO2 ratio < 0.10 |
Prophylaxis Trial
A total of 853 infants < 29 weeks gestation were enrolled
into a multiple-dose, randomized, double-blind prophylaxis trial comparing
Infasurf (3mL/kg) and Exosurf Neonatal® (5mL/kg). The initial dose was
administered within 30 minutes of birth. Repeat doses were administered at 12
and 24 hours if the patient remained intubated. Each dose was administered
divided in 2 equal aliquots, and given through a side port adapter into the
proximal end of the endotracheal tube. Each aliquot was given in small bursts
over 20-30 inspiratory cycles. After each aliquot was instilled, the infant was
positioned with either the right or the left side dependent. Results for
efficacy parameters evaluated to day 28 or to discharge for all treated
patients from this prophylaxis trial are shown in Table 2.
Table 2 - Infasurf vs Exosurf Neonatal® Prophylaxis Trial
| EfficacyParameter |
Infasurf
(N=431)
% |
Exosurf
Neonatal®
(N=422)
% |
p-Value |
| Incidence of RDS |
15 |
47 |
≤ 0.001 |
| Incidence of air leaksa |
10 |
15 |
0.01 |
| Death due to RDS |
2 |
5 |
≤ 0.01 |
| Any death to 28 days |
12 |
16 |
0.10 |
| Any death before discharge |
18 |
19 |
0.56 |
| BPDb |
16 |
17 |
0.60 |
| Crossover to other surfactantc |
0.2 |
3 |
≤ 0.001 |
a Pneumothorax and/or pulmonary interstitial emphysema.
b BPD is bronchopulmonary dysplasia, diagnosed by positive X-ray and oxygen dependence at 28 days.
c Protocol permitted use of comparator surfactant in patients who failed to respond to therapy with the initial randomized surfactant if the infant was < 72 hours of age, had received a full course of the randomized surfactant, and had an a/A PO2 ratio < 0.10 |
Infasurf versus Survanta®
Treatment Trial
A total of 662 infants with RDS who required endotracheal
intubation and had an a/A PO2 < 0.22 were enrolled into a
multiple-dose, randomized, double-blind treatment trial comparing Infasurf
(4mL/kg of a formulation that contained 25 mg of phospholipids/mL rather than
the 35 mg/mL in the marketed formulation) and Survanta® (4mL/kg). Repeat doses
were allowed ≥ 6 hours following the previous treatment (for up to three
doses before 96 hours of age) if the patient required ≥ 30% oxygen. The
surfactant was given through a 5 French feeding catheter inserted into the
endotracheal tube. The total dose was instilled in four equal aliquots with the
catheter removed between each of the instillations and mechanical ventilation
resumed for 0.5 to 2 minutes. Each of the aliquots was administered with the patient
in one of four different positions (prone, supine, right, and left lateral) to
facilitate even distribution of the surfactant. Results for the major efficacy
parameters evaluated at 28 days or to discharge (incidence of air leaks, death due
to respiratory causes or to any cause, BPD, or treatment failure) for all treated
patients from this treatment trial were not significantly different between
Infasurf and Survanta®.
Prophylaxis Trial
A total of 457 infants ≤ 30 weeks gestation and
< 1251 grams birth weight were enrolled into a multiple-dose, randomized, double-blind
trial comparing Infasurf (4mL/kg of a formulation that contained 25 mg of
phospholipids/mL rather than the 35 mg/mL in the marketed formulation) and
Survanta® (4mL/kg). The initial dose was administered within 15 minutes of
birth and repeat doses were allowed ≥ 6 hours following the previous
treatment (for up to three doses before 96 hours of age) if the patient
required ≥ 30% oxygen. The surfactant was given through a 5 French feeding
catheter inserted into the endotracheal tube. The total dose was instilled in four
equal aliquots with the catheter removed between each of the instillations and
mechanical ventilation resumed for 0.5 to 2 minutes. Each of the aliquots was
administered with the patient in one of four different positions (prone,
supine, right, and left lateral). Results for efficacy endpoints evaluated at
28 days or to discharge for all treated patients from this prophylaxis trial showed
an increase in mortality from any cause at 28 days (p=0.03) and in death due to
respiratory causes (p=0.005) in Infasurf-treated infants. For evaluable
patients (patients who met the protocol-defined entry criteria), mortality from
any cause and mortality due to respiratory causes were also higher in the
Infasurf group (p = 0.07 and 0.03, respectively). However, these observations
have not been replicated in other adequate and well-controlled trials and their
relevance to the intended population is unknown. All other efficacy outcomes
(incidence of RDS, air leaks, BPD, and treatment failure) were not
significantly different between Infasurf and Survanta® when analyzed for all
treated patients and for evaluable patients.
Acute Clinical Effects
As with other surfactants, marked improvements in
oxygenation and lung compliance may occur shortly after the administration of Infasurf.
All controlled clinical trials with Infasurf demonstrated significant
improvements in fraction of inspired oxygen (FiO2) and
mean airway pressure (MAP) during the first 24 to 48 hours following initiation
of Infasurf therapy.
Last updated on RxList: 5/7/2009