Survanta

Beractant.

Each mL of single-use vial contains phospholipids 25 mg (phospholipids 200 mg/8 mL) suspended in 0.9% sodium chloride solution.
Survanta (beractant) intratracheal suspension is a sterile, nonpyrogenic pulmonary surfactant intended for intratracheal use only. It is a natural bovine lung extract containing phospholipids, neutral lipids, fatty acids and surfactant-associated proteins to which colfosceril palmitate (dipalmitoylphosphatidylcholine), palmitic acid and tripalmitin are added to standardize the composition and to mimic surface-tension lowering properties of natural lung surfactant. The resulting composition provides phospholipids 25 mg/mL (including disaturated phosphatidylcholine 11-15.5 mg/mL), triglycerides 0.5-1.75 mg/mL, free fatty acids 1.4-3.5 mg/mL and protein <1 mg/mL. It is suspended in 0.9% sodium chloride solution and heat-sterilized. Survanta contains no preservatives. Its protein content consists of 2 hydrophobic, low molecular weight, surfactant-associated proteins commonly known as SP-B and SP-C. It does not contain the hydrophilic, large molecular weight, surfactant-associated protein known as SP-A.

Pharmacology: Endogenous pulmonary surfactant lowers surface tension on alveolar surfaces during respiration and stabilizes the alveoli against collapse at resting transpulmonary pressures. Deficiency of pulmonary surfactant causes respiratory distress syndrome (RDS) in premature infants. Survanta replenishes surfactant and restores surface activity to the lungs of these infants.
Activity: In vitro, Survanta reproducibly lowers minimum surface tension to <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 doses of Survanta improve lung pressure-volume measurements, lung compliance and oxygenation in premature rabbits and sheep.
Animal Metabolism: 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 radiolabelled 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.
Clinical Studies: Clinical effects of Survanta were demonstrated in 6 single-dose and 4 multiple-dose randomized, multicenter, controlled clinical trials involving approximately 1700 infants. Three open trials, including a treatment IND, involved >4800 infants. Each dose of Survanta in all studies was phospholipids 100 mg/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 600-1250 g birth weight and 23-29 weeks estimated gestational age were enrolled in 2 multiple-dose studies. A dose of Survanta was given within 15 min of birth to prevent the development of RDS. Up to 3 additional doses in the first 48 hrs, as often as every 6 hrs, were given if RDS subsequently developed and infants required mechanical ventilation with an FiO₂ ≥0.3. Results of the studies at 28 days of age are shown in Table 1.

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Rescue Studies: Infants of 600-1750 g birth weight with RDS requiring mechanical ventilation and an FiO₂ ≥0.4 were enrolled in 2 multiple-dose rescue studies. The initial dose of Survanta was given after RDS developed and before 8 hrs of age. Infants could receive up to 3 additional doses in the first 48 hrs, as often as every 6 hrs, if they required mechanical ventilation and an FiO₂ ≥0.3. Results of the studies at 28 days of age are shown in Table 2.

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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 48-72 hrs of life. Significant improvements in these variables were sustained for 48-72 hrs in Survanta-treated infants in 4 single-dose and 2 multiple-dose rescue studies and in 2 multiple-dose prevention studies. In the single-dose prevention studies, the FiO₂ improved significantly.

Prevention and treatment ("rescue") of respiratory distress syndrome (RDS) (hyaline membrane disease) in premature infants. Survanta significantly reduces the incidence of RDS, mortality due to RDS and air leak complications.
Prevention: In premature infants <1250 g birth weight or with evidence of surfactant deficiency, give Survanta as soon as possible, preferably within 15 min of birth.
Rescue: To treat infants with RDS confirmed by x-ray and requiring mechanical ventilation, give Survanta as soon as possible, preferably by 8 hrs of age.

For intratracheal administration only.
Survanta should be administered by or under the supervision of clinicians experienced in intubation, ventilator management and general care of premature infants.
Marked improvements in oxygenation may occur within minutes of administration of Survanta. Therefore, frequent and careful clinical observation and monitoring of systemic oxygenation are essential to avoid hyperoxia.
Review of audiovisual instructional materials describing dosage and administration procedures is recommended before using Survanta.
Dosage: Each dose of Survanta is phospholipids 100 mg/kg birth weight (4 mL/kg).
The Survanta Dosing Chart shows the total dosage for a range of birth weights. (See Table 3.)

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Four doses of Survanta can be administered in the first 48 hrs of life. Doses should be given no more frequently than every 6 hrs.
Administration: General: Survanta is administered intratracheally by instillation through a 5 French end-hole catheter inserted into the infant's endotracheal tube with the tip of the catheter protruding just beyond the end of the endotracheal tube above the infant's carina. Before inserting the catheter through the endotracheal tube, the length of the catheter should be shortened. Survanta should not be instilled into a main-stem bronchus.
It is important to ensure homogenous distribution of Survanta throughout the lungs. In the controlled clinical trials, each dose was divided into 4 quarter doses. Each quarter-dose was administered with the infant in a different position. The sequence of positions was: (1) Head and body inclined slightly down, head turned to the right; (2) Head and body inclined slightly down, head turned to the left; (3) Head and body inclined slightly up, head turned to the right; and (4) Head and body inclined slightly up, head turned to the left.
The dosing procedure is facilitated if 1 person administers the dose while another person positions and monitors the infant.
First Dose: Determine the total dose of Survanta from the Survanta dosing chart based on the infant's birth weight. Slowly withdraw the entire contents of the vial into a plastic syringe through a large gauge needle (eg, at least 20 gauge). Do not filter Survanta and avoid shaking.
Attach the premeasured 5 French end-hole catheter to the syringe. Fill the catheter with Survanta. Discard excess Survanta through the catheter so that only the total dose to be given remains in the syringe.
Before administering Survanta, assure proper placement and patency of the endotracheal tube. At the discretion of the clinician, the endotracheal tube may be suctioned before administering Survanta. The infant should be allowed to stabilize before proceeding with dosing.
In the prevention strategy, weigh, intubate and stabilize the infant. Administer the dose as soon as possible after birth, preferably within 15 min. Position the infant appropriately and gently inject the first quarter-dose through the catheter over 2-3 sec.
After administration of the first quarter-dose, remove the catheter from the endotracheal tube. Manually ventilate with a hand-bag with sufficient oxygen to prevent cyanosis, at a rate of 60 breaths/min, and sufficient positive pressure to provide adequate air exchange and chest wall excursion.
In the rescue strategy, the first dose should be given as soon as possible after the infant is placed on a ventilator for management of RDS. In the clinical trials, immediately before instilling the first quarter-dose, the infant's ventilator settings were changed to rate 60/min, inspiratory time 0.5 sec and FiO₂ 1.0.
Position the infant appropriately and gently inject the first quarter-dose through the catheter over 2-3 sec. After administration of the first quarter-dose, remove the catheter from the endotracheal tube. Return the infant to the mechanical ventilator.
In both strategies, ventilate the infant for at least 30 sec or until stable. Reposition the infant for instillation of the next quarter-dose.
Instill the remaining quarter-doses using the same procedures. After instillation of each quarter-dose, remove the catheter and ventilate for at least 30 sec or until the infant is stabilized. After instillation of the final quarter-dose, remove the catheter without flushing it. Do not suction the infant for 1 hr after dosing unless signs of significant airway obstruction occur.
After completion of the dosing procedure, resume usual ventilator management and clinical care.
Repeat Doses: The dosage of Survanta for repeat doses is also 100 mg phospholipids/kg and is based on the infant's birth weight. The infant should not be reweighed for determination of the dosage. Use the Survanta dosing chart to determine the total dosage.
The need for additional doses is determined by evidence of continuing respiratory distress. Using the following criteria for redosing, significant reductions in mortality due to RDS were observed in the multiple-dose clinical trials with Survanta.
Dose no sooner than 6 hrs after the preceding dose if the infant remains intubated and requires at least 30% inspired oxygen to maintain a PaO₂ ≤80 torr.
Radiographic confirmation of RDS should be obtained before administering additional doses to those who received a prevention dose.
Prepare Survanta and position the infant for administration of each quarter-dose as previously described. After instillation of each quarter-dose, remove the dosing catheter from the endotracheal tube and ventilate the infant for at least 30 sec or until stable.
In the clinical studies, ventilator settings used to administer repeat doses were different than those used for the first dose. For repeat doses, the FiO₂ was increased by 0.2 or an amount sufficient to prevent cyanosis. The ventilator delivered a rate of 30/min with an inspiratory time <1 sec. If the infant's pre-treatment rate was ≥30, it was left unchanged during Survanta instillation.
Manual hand-bag ventilation should not be used to administer repeat doses. During the dosing procedure, ventilator settings may be adjusted at the discretion of the clinician to maintain appropriate oxygenation and ventilation.
After completion of the dosing procedure, resume usual ventilator management and clinical care.
Dosing Precautions: If an infant experiences bradycardia or oxygen desaturation during the dosing procedure, stop the dosing procedure and initiate appropriate measures to alleviate the condition. After the infant has stabilized, resume the dosing procedure.
Rales and moist breath sounds can occur transiently after administration of Survanta. Endotracheal suctioning or other remedial action is unnecessary unless clear-cut signs of airway obstruction are present.

Overdosage with Survanta has not been reported. Based on animal data, overdosage might result in acute airway obstruction. Treatment should be symptomatic and supportive.
Rales and moist breath sounds can transiently occur after Survanta is given, and do not indicate overdosage. Endotracheal suctioning or other remedial action is not required unless clear-cut signs of airway obstruction are present.

None known.

Survanta is intended for intratracheal use only.
Survanta can rapidly affect oxygenation and lung compliance. Therefore, its use should be restricted to a highly supervised clinical setting with immediate availability of clinicians experienced with intubation, ventilator management and general care of premature infants. Infants receiving Survanta should be frequently monitored with arterial or transcutaneous measurement of systemic oxygen and carbon dioxide.
During the dosing procedure, transient episodes of bradycardia and decreased oxygen saturation have been reported. If these occur, stop the dosing procedure and initiate appropriate measures to alleviate the condition. After stabilization, resume the dosing procedure.

General: Rales and moist breath sounds can occur transiently after administration. Endotracheal suctioning or other remedial action is not necessary unless clear-cut signs of airway obstruction are present.
Increased probability of post-treatment nosocomial sepsis in Survanta-treated infants was observed in the controlled clinical trials (see Table 4). The increased risk for sepsis among Survanta-treated infants was not associated with increased mortality among these infants. The causative organisms were similar in treated and control infants. There was no significant difference between groups in the rate of post-treatment infections other than sepsis.
Use of Survanta in infants <600 g birth weight or >1750 g birth weight has not been evaluated in controlled trials. There is no controlled experience with the use of Survanta in conjunction with experimental therapies for RDS (eg, high-frequency ventilation or extracorporeal membrane oxygenation).
No information is available on the effects of doses other than phospholipids 100 mg/kg, >4 doses, dosing more frequently than every 6 hrs or administration after 48 hrs of age.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Reproduction studies in animals have not been completed. Mutagenicity studies were negative. Carcinogenicity studies have not been performed with Survanta.

The most commonly reported adverse experiences were associated with the dosing procedure. In the multiple-dose controlled clinical trials, transient bradycardia occurred with 11.9% of doses. Oxygen desaturation occurred with 9.8% of doses.
Other reactions during the dosing procedure occurred with fewer than 1% of doses and included endotracheal tube reflux, pallor, vasoconstriction, hypotension, endotracheal tube blockage, hypertension, hypocarbia, hypercarbia and apnea. No deaths occurred during the dosing procedure and all reactions resolved with symptomatic treatment.
The occurrence of concurrent illnesses common in premature infants was evaluated in the controlled trials. The rates in all controlled studies are in Table 4.

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When all controlled studies were pooled, there was no difference in intracranial hemorrhage. However, in one of the single-dose rescue studies and one of the multiple-dose prevention studies, the rate of intracranial hemorrhage was significantly higher in Survanta patients than control patients (63.3% vs 30.8%, P=0.001; and 48.8% vs 34.2%, P=0.047, respectively). The rate in a treatment IND involving approximately 4400 infants was lower than in the controlled trials.
In the controlled clinical trials, there was no effect of Survanta on results of common laboratory tests: White blood cell count and serum sodium, potassium, bilirubin, creatinine.
More than 3700 pre- and post-treatment serum samples were tested by Western blot immunoassay for antibodies to surfactant-associated proteins SP-B and SP-C. No IgG or IgM antibodies were detected.
Several other complications are known to occur in premature infants. The following conditions were reported in the controlled clinical studies. The rates of the complications were not different in treated and control infants, and none of the complications were attributed to Survanta.
Respiratory: Lung consolidation, blood from the endotracheal tube, deterioration after weaning, respiratory decompensation, subglottic stenosis, paralyzed diaphragm, respiratory failure.
Cardiovascular: Hypotension, hypertension, tachycardia, ventricular tachycardia, aortic thrombosis, cardiac failure, cardiorespiratory arrest, increased apical pulse, persistent fetal circulation, air embolism, total anomalous pulmonary venous return.
Gastrointestinal: Abdominal distention, hemorrhage, intestinal perforations, volvulus, bowel infarct, feeding intolerance, hepatic failure, stress ulcer.
Renal: Renal failure, hematuria.
Hematologic: Coagulopathy, thrombocytopenia, disseminated intravascular coagulation.
Central Nervous System: Seizures.
Endocrine/Metabolic: Adrenal hemorrhage, inappropriate antidiuretic hormone (ADH) secretion, hyperphosphatemia.
Musculoskeletal: Inguinal hernia.
Systemic: Fever, deterioration.
Follow-Up Evaluations: To date, no long-term complications or sequelae of Survanta therapy have been found.
Single-Dose Studies: Six-month adjusted-age follow-up evaluations of 232 infants (115 treated) demonstrated no clinically important differences between treatment groups in pulmonary and neurologic sequelae, incidence or severity of retinopathy of prematurity, re-hospitalizations, growth or allergic manifestations.
Multiple-Dose Studies: Six-month adjusted-age follow-up evaluations have not been completed. Preliminarily, in 605 (333 treated) of 916 surviving infants, there are trends for decreased cerebral palsy and need for supplemental oxygen in Survanta infants. Wheezing at the time of examination tended to be more frequent among Survanta infants, although there was no difference in bronchodilator therapy.
Twelve-month follow-up data from the multiple-dose studies have been completed in 328 (171 treated) of 909 surviving infants. To date no significant differences between treatments have been found, although there is a trend toward less wheezing in Survanta infants in contrast to the 6-month results.

Survanta should be inspected visually for discoloration prior to administration. The color of Survanta is off-white to light brown. If settling occurs during storage, swirl the vial gently (do not shake) to redisperse. Some foaming at the surface may occur during handling and is inherent in the nature of Survanta.
Survanta is stored refrigerated (2-8°C). Before administration, it should be warmed by standing at room temperature for at least 20 min or warmed in the hand for at least 8 min. Artificial warming methods should not be used. If a prevention dose is to be given, preparation of Survanta should begin before the infant's birth.
Unopened, unused vials of Survanta that have been warmed to room temperature may be returned to the refrigerator within 8 hrs of warming, and stored for future use. Survanta should not be warmed and returned to the refrigerator more than once. Each single-use vial of Survanta should be entered only once. Used vials with residual drug should be discarded.
Survanta does not require reconstitution or sonication before use.

Store unopened vials at refrigeration temperature (2-8°C). Protect from light. Store vials in carton until ready for use. Vials are for single use only. Upon opening, discard unused drug.

Other Drugs Acting on the Respiratory System

R07AA02 - natural phospholipids ; Belongs to the class of lung surfactants. Used in the treatment of respiratory diseases.
R07AA30 - combinations ; Belongs to the class of lung surfactants. Used in the treatment of respiratory diseases.

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