Survanta

SURVANTA Intratracheal Suspension is supplied in single-use glass vials. Each milliliter contains 25 mg of phospholipids suspended in 0.9% sodium chloride solution. The color is off-white to light brown.
SURVANTA Intratracheal Suspension is a sterile, non-pyrogenic pulmonary surfactant and natural bovine lung extract. It is supplemented with three synthetically derived lipids 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 an average concentration of 25 mg/ml phospholipids and less than 1.0 mg/ml protein. The formulation is an off-white to light brown opaque liquid.
Chemistry: The following are the specified ranges for the lipid and protein components of SURVANTA.
Total Phospholipids: approximately 25 mg/ml.
Free Fatty Acids: 1.4 to 3.5 mg/ml.
Triglycerides: 0.5 to 1.75 mg/ml.
Protein: 0.1 to 1.0 mg/ml.
The components are suspended in 0.9% sodium chloride solution and heat-sterilized. SURVANTA contains no preservatives. Its protein content consists of two 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: Mechanism of Action: Endogenous pulmonary surfactant lowers surface tension of 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.
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.)

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Rescue 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.)

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Fractional 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.

SURVANTA is indicated for 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.

Important Administration Instructions: 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. The dosing procedure is facilitated if one person administers the dose while another person positions and monitors the infant.
Dosage: Each dose of SURVANTA is 100 mg of phospholipids/kg birth weight (4 ml/kg).
In the prevention strategy, administer the dose as soon as possible after birth, preferably within 15 minutes.
In the rescue strategy, the first dose should be given as soon as possible after RDS is confirmed by radiographic or clinical findings, preferably by eight hours of age.
Four doses of SURVANTA can be administered in the first 48 hours of life. Doses should be given no more frequently than every six hours.
The need for additional doses of SURVANTA is determined by evidence of continuing respiratory distress. Radiographic confirmation of RDS should be obtained before administering additional doses to those who received a prevention dose.
Preparation of the SURVANTA Suspension: SURVANTA should be inspected visually for discoloration prior to administration. The colour of SURVANTA is off-white to light brown.
If settling occurs during storage, swirl the vial gently (DO NOT SHAKE) to redisperse. Do not filter SURVANTA. Some foaming at the surface may occur during handling and is inherent in the nature of the product.
SURVANTA is stored refrigerated (2 to 8°C). Before administration, SURVANTA should be warmed by standing at room temperature for at least 20 minutes or warmed in the hand for at least eight minutes. 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 24 hours 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.
General Dosing Procedures: Based on the selected procedure, each dose is either given as a single bolus or is divided into fractional doses.
Each fractional dose can be administered in two half-doses or in four quarter-doses with the infant in a different position.
To administer SURVANTA in two half-doses, the recommended positions are: Head and body turned approximately 45° to the right.
Head and body turned approximately 45° to the left.
To administer SURVANTA in four quarter-doses, the recommended positions are: Head and body inclined 5-10° down, head turned to the right.
Head and body inclined 5-10° down, head turned to the left.
Head and body inclined 5-10° up, head turned to the right.
Head and body inclined 5-10° up, head turned to the left.
The positions for four quarter-doses are stated as follows: 1. Infant's head and body inclined down, head turned to the right.
2. Head and body inclined down, head turned to the left.
3. Head and body inclined up, head turned to the right.
4. Head and body inclined up. head turned to the left.
Administration: Instillation Through End-Hole Catheter in Mechanically Ventilated Patients: Slowly withdraw the entire contents of the vial into a plastic syringe through a large-gauge needle (e.g., at least 20 gauge).
Attach the pre-measured 5 French end-hole catheter to the syringe. Fill the catheter with SURVANTA. Discard excess beractant through the catheter so 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.
Position the infant appropriately in one of the recommended positions.
Insert the 5 French end-hole catheter into the endotracheal tube. The length of the catheter should be shortened so that the tip of the catheter protrudes just beyond the endotracheal tube above the infant's carina. SURVANTA should not be instilled into a mainstem bronchus.
Gently inject the first fractional dose through the catheter over two to three seconds.
After administration of the first fractional dose, remove the catheter from the endotracheal tube and manually ventilate the infant for 30 seconds or until clinically stable. Ventilate with sufficient oxygen to prevent cyanosis and sufficient positive pressure to provide adequate air exchange and chest wall excursion.
When the infant is stable, reposition the infant for instillation of the next fractional dose.
Instill the remaining fractional doses using the same procedures.
After instillation of the final fractional dose, remove the catheter without flushing it. Do not suction the infant for one hour after dosing unless signs of significant airway obstruction occur.
Instillation Through Secondary Lumen of a Double-Lumen Endotracheal Tube in Mechanically Ventilated Patients: Ensure the infant is intubated with the appropriate size double-lumen endotracheal tube. Slowly withdraw the total dose from the vial into a plastic syringe through a large-gauge needle (e.g., at least 20 gauge).
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.
Attach the syringe containing SURVANTA to the secondary lumen. Position the infant appropriately in one of the recommended positions and gently inject the first fractional dose through the secondary lumen over two to three seconds without interrupting ventilation. If manually ventilated, ventilate the infant for at least 30 seconds or until stable. Ventilate with sufficient oxygen to prevent cyanosis and sufficient positive pressure to provide adequate air exchange and chest wall excursion.
Reposition the infant for instillation of the next fractional dose.
Instill the remaining fractional doses using the same procedures.
After instillation of the final fractional dose, remove the syringe from the secondary lumen, inject 0.5 mL of air to flush the secondary lumen and cap it.
Instillation in Spontaneously Breathing Patients: Intubation Surfactant Extubation (INSURE): Following intubation and catheterization as described previously, place the infant in a neutral position and gently inject the dose as a single bolus over 1 to 3 minutes in the delivery room or later after admission to the neonatal unit. After instillation, use a bagging technique and proceed to extubation and CPAP as clinically indicated.
Less Invasive Surfactant Administration (LISA): A small diameter catheter may be used to administer the dose without intubation. In such cases, place the catheter directly into the trachea with visualization of the vocal cords by laryngoscopy and gently inject the dose as a single bolus over 1 to 3 minutes. After instillation, immediately remove the catheter. Ensure continuous spontaneous breathing and continue CPAP treatment during the entire procedure.

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 3 under Adverse Reactions). 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 less than 600 g birth weight or greater than 1750 g birth weights has not been evaluated in controlled trials. There is no controlled experience with the use of SURVANTA in conjunction with experimental therapies for RDS (e.g. high-frequency ventilation or extracorporeal membrane oxygenation).
No information is available on the effects of doses other than 100 mg phospholipids/kg, more than four doses, dosing more frequently than every six hours, or administration after 48 hours of age.

Clinical Trials: Mechanically Ventilated Patients: The most commonly reported adverse experiences were associated with the dosing procedure.
In the multiple-dose controlled clinical trials, each dose of SURVANTA was divided into four quarter- doses. Each quarter dose was instilled through a catheter inserted into the endotracheal tube by briefly disconnecting the endotracheal tube from the ventilator. 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.
A clinical study compared the previously noted quarter-dose administration regimen to the administration of two half-doses with interrupted ventilation as described previously and the administration of two half-doses accomplished by passing the catheter through a neonatal suction valve in the endotracheal tube, with uninterrupted ventilation. With the first dose, there was significantly less endotracheal tube reflux observed in the group with the quarter-dose regimen (p=.007) than in the group with uninterrupted ventilation. With the first dose there was significantly less oxygen desaturation in the group with uninterrupted ventilation (p=.008) than in the other group receiving two half-doses. There were no differences in these events after later doses and no differences in heart rate after any doses (see General Dosing Procedures under Dosage & Administration).
The occurrence of concurrent illnesses common in premature infants was evaluated in the controlled trials. The rates in all controlled studies are in Table 3. (See Table 3.)

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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% versus 30.8%, P = 0.001; and 48.8% versus 34.2%, P = 0.047, respectively). The rate in a Treatment IND involving approximately 8100 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, and creatinine.
More than 4300 pre-treatment and post-treatment serum samples from approximately 1500 patients 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.
Blood and lymphatic system disorders: Coagulopathy, thrombocytopenia, disseminated intravascular coagulation.
Endocrine disorders: Adrenal hemorrhage, inappropriate ADH secretion.
Metabolism and nutrition disorders: Hyperphosphatemia, feeding intolerance.
Nervous system disorders: Seizures.
Cardiac disorders: Tachycardia, ventricular tachycardia, cardiac failure, cardio-respiratory arrest, increased apical pulse, persistent fetal circulation, total anomalous pulmonary venous return.
Vascular disorders: Hypotension, hypertension, aortic thrombosis, air embolism.
Respiratory, thoracic and mediastinal disorders: Lung consolidation, blood from the endotracheal tube, deterioration after weaning, respiratory decompensation, subglottic stenosis, paralyzed diaphragm, respiratory failure.
Gastrointestinal disorders: Abdominal distension, gastrointestinal hemorrhage, intestinal perforations, volvulus, bowel infarct, stress ulcer, inguinal hernia.
Hepatobiliary disorders: Hepatic failure.
Renal and urinary disorders: Renal failure, haematuria.
General disorders and administration site conditions: Fever, deterioration.
Post Marketing Experience: 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, rehospitalizations, growth, or allergic manifestations.
Multiple-Dose Studies: Six-month adjusted-age follow-up evaluations have been completed in 631 (345 treated) of 916 surviving infants. There was significantly less cerebral palsy and need for supplemental oxygen in SURVANTA infants than controls. Wheezing at the time of examination was more frequent among SURVANTA infants, although there was no difference in bronchodilator therapy.
Final twelve-month follow-up data from the multiple-dose studies are available from 521 (272 treated) of 909 surviving infants. There was significantly less wheezing in SURVANTA infants than controls in contrast to the six-month results. There was no difference in the incidence of cerebral palsy at twelve months.
Twenty-four month adjusted age evaluations were completed in 429 (226 treated) of 906 surviving infants. There were significantly fewer SURVANTA infants with rhonchi, wheezing, and tachypnea at the time of examination. No other differences were found.
INSURE and LISA Techniques: Safety results with the INSURE and LISA techniques were comparable to those of the control groups, although bradycardia and hypoxemia were reported more frequently in some cases with LISA.

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

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