INFASURF Suspension Ref.[11113] Active ingredients: Beractant

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 less than or equal to 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 and25% 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 less than or equal to 72 hours of age with RDS who required endotracheal intubation and had an a/A PO2 less than 0.22 were enrolled into a multiple-dose, randomized, double-blind treatment trial comparing Infasurf (3 mL/kg) and Exosurf Neonatal (5 mL/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:

^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 less than 96 hours of age, had received a full course of the randomized surfactant, and had an a/A PO2 ratio less than 0.10

Prophylaxis Trial

A total of 853 infants less than 29 weeks gestation were enrolled into a multiple-dose, randomized, double-blind prophylaxis trial comparing Infasurf (3 mL/kg) and Exosurf Neonatal (5 mL/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 endotra cheal 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:

^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 less than 72 hours of age, had received a full course of the randomized surfactant, and had an a/A PO2 ratio less than 0.10

Infasurf versus Survanta

Treatment Trial

A total of 662 infants with RDS who required endotracheal intubation and had an a/A PO2 less than 0.22 were enrolled into a multiple-dose, randomized, double-blind treatment trial comparing Infasurf (4 mL/kg of a formulation that contained 25 mg of phospholipids/mL rather than the 35 mg/mL in the marketed formulation) and Survanta (4 mL/kg). Repeat doses were allowed Greater than or equal to 6 hours following the previous treatment (for up to three doses before 96 hours of age) if the patient required Greater than or equal to 30% oxygen. The surfactant was given through a 5 French feeding catheter inserted into the endo tracheal 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 less than or equal to 30 weeks gestation and less than 1251 grams birth weight were enrolled into a multiple-dose, randomized, double-blind trial comparing Infasurf (4 mL/kg of a formulation that contained 25 mg of phospholipids/mL rather than the 35 mg/mL in the marketed formulation) and Survanta (4 mL/kg). The initial dose was administered within15 minutes of birth and repeat doses were allowed Greater than or equal to 6 hours following the previous treatment (for up to three doses before 96 hours of age) if the patient required Greater than or equal to 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.