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Pharmacodynamics: In vitro, SURVANTA reproducibly lowers minimum surface tension to less than 8 dynes/cm, as measured by the pulsating bubble surfactometer and Wilhelmy Surface Balance. In situ, SURVANTA restores pulmonary compliance to excised rat lungs artificially made surfactant-deficient. In vivo, single SURVANTA doses improve lung pressure-volume measurements, lung compliance, and oxygenation in premature rabbits and sheep.
Clinical Studies: Mechanically Ventilated Patients: Clinical effects of SURVANTA were demonstrated in six single-dose and four multiple-dose randomized, multi-center, controlled clinical trials involving approximately 1700 infants. Three open trials, including a Treatment IND, involved more than 8500 infants. Each dose of SURVANTA in all studies was 100 mg phospholipids/kg birth weight and was based on published experience with Surfactant TA, a lyophilized powder dosage form of SURVANTA having the same composition.
Prevention Studies: Infants of 600 to 1250 g birth weight and 23 to 29 weeks estimated gestational age were enrolled in two multiple-dose studies. A dose of SURVANTA was given within 15 minutes of birth to prevent the development of RDS. Up to three additional doses in the first 48 hours, as often as every six hours, were given if RDS subsequently developed and infants required mechanical ventilation with an FiO2 ≥0.30. Results of the studies at 28 days of age are shown in Table 1. (See Table 1.)
Click on icon to see table/diagram/imageRescue Studies: Infants of 600 to 1750 g birth weight with RDS requiring mechanical ventilation and an FiO2 ≥0.40 were enrolled in two multiple-dose rescue studies. The initial dose of SURVANTA was given after RDS developed and before eight hours of age. Infants could receive up to three additional doses in the first 48 hours, as often as every six hours, if they required mechanical ventilation and an FiO2 ≥0.30. Results of the studies at 28 days of age are shown in Table 2. (See Table 2.)
Click on icon to see table/diagram/imageFractional Doses: In the clinical trials that established safety and efficacy, beractant was instilled through a catheter that was inserted into the infant's endotracheal tube by briefly disconnecting the endotracheal tube from the ventilator. Each dose was administered in four quarter-doses as described previously. This method of administering beractant was compared to two other methods in a multi-center, randomized clinical study involving 299 infants weighing 600 g or more with RDS requiring mechanical ventilation. The other methods evaluated were: Two half-doses administered by inserting the catheter through the endotracheal tube while the endotracheal tube was briefly disconnected from the ventilator. The half-doses were administered in the two positions described previously.
Two half-doses administered without disconnecting the endotracheal tube from the ventilator by inserting the catheter through a neonatal suction valve into the endotracheal tube. The half-doses were administered in the two positions described previously.
There were no significant differences among the three groups in average FiO2, a/APO2, or MAP at 72 hours of age, or in the incidence of pulmonary air leaks, pulmonary interstitial emphysema, patent ductus arteriosus, or mortality at 72 hours of age.
LISA Technique: The LISA method of administration was evaluated in two multicenter and seven single-center studies. A total of 745 infants were treated with SURVANTA via LISA with an additional 583 infants treated with SURVANTA via endotracheal tube as control groups. All infants were administered a dose of 100 mg/kg birth weight. Individual study mean gestational ages ranged from 25.3 weeks to 32 weeks with mean weights ranging from 610 g to 1865 g. Infants treated with CPAP and LISA had a reduced need for mechanical ventilation, reduced duration of mechanical ventilation, reduced oxygen requirement, reduced need for analgesics and sedatives, and reduced risk of development of bronchopulmonary dysplasia due to RDS.
Acute Clinical Effects: Marked improvements in oxygenation may occur within minutes of administration of SURVANTA.
All controlled clinical studies with SURVANTA provided information regarding the acute effects of SURVANTA on the arterial-alveolar oxygen ratio (a/APO2), FiO2, and mean airway pressure (MAP) during the first 48 to 72 hours of life. Significant improvements in these variables were sustained for 48 to 72 hours in SURVANTA-treated infants in four single-dose and two multiple-dose rescue studies and in two multiple-dose prevention studies. In the single-dose prevention studies, the FiO2 improved significantly.
Pharmacokinetics: SURVANTA is administered directly to the target organ, the lungs, where biophysical effects occur at the alveolar surface. In surfactant-deficient premature rabbits and lambs, alveolar clearance of radio-labeled lipid components of SURVANTA is rapid. Most of the dose becomes lung-associated within hours of administration, and the lipids enter endogenous surfactant pathways of reutilization and recycling. In surfactant-sufficient adult animals, SURVANTA clearance is more rapid than in premature and young animals. There is less reutilization and recycling of surfactant in adult animals.
Limited animal experiments have not found effects of SURVANTA on endogenous surfactant metabolism. Precursor incorporation and subsequent secretion of saturated phosphatidylcholine in premature sheep are not changed by SURVANTA treatments.
No information is available about the metabolic fate of the surfactant-associated proteins in SURVANTA. The metabolic disposition in humans has not been studied.
Toxicology: Pre-clinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: SURVANTA up to 500 mg phospholipids/kg/day was administered subcutaneously to newborn rats for five days. The rats reproduced normally and there were no observable adverse effects in their offspring.
Mutagenicity studies were negative. Carcinogenicity studies have not been performed with SURVANTA.
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