Survanta (Beractant)

SURVANTA®

Abbott

Beractant

Lung Surfactant

Action and Clinical

Deficiency of pulmonary surfactant is an important factor in the development of Respiratory Distress Syndrome (RDS) in premature infants. Beractant replenishes surfactant and restores surface activity to the lungs of these infants. It reduces surface tension and concomitantly increases lung compliance.:

Intratracheally administered beractant distributes rapidly to the alveolar surfaces and stabilizes the alveoli against collapse during respiration thereby increasing alveolar ventilation.

In clinical studies of premature infants with RDS, a significant improvement in oxygenation was demonstrated after treatment with a single dose of beractant. These infants showed a decreased need for supplemental oxygen and an increase in the arterial/alveolar oxygen ratio (a/Ap0 2). Significantly decreased need for respiratory support, as indicated by a lower mean airway pressure, was also observed.

In prophylactic studies of premature infants at high risk of RDS, multiple doses (up to 4 doses within 48 hours) of beractant reduced the incidence and mortality of RDS, reduced the incidence of pulmonary air leaks and pulmonary interstitial emphysema, improved a/Ap0 2 and Fi0 2 (Fraction of inspired oxygen) at 72 hours of age, and reduced mortality from any cause.

No information is available about the metabolic fate of the surfactant-associated proteins in beractant. The metabolic disposition in humans has not been studied.

Indications And Clinical Uses:

For prevention (prophylaxis) and treatment (rescue) of Respiratory Distress Syndrome (RDS/Hyaline Membrane Disease) in premature infants.

For prophylactic treatment of infants at risk of developing RDS or who have evidence of pulmonary immaturity.

In premature infants less than 1 250 g birthweight or with evidence of surfactant deficiency, give beractant as soon as possible after an airway has been established, preferably within 15 minutes of birth.

For rescue treatment of infants who have developed RDS. To treat infants with RDS confirmed by x-ray and who require mechanical ventilation, give beractant as soon as possible after an airway has been established, preferably by 8 hours of age.

Beractant significantly reduces the incidence of RDS, mortality due to RDS and air leak complications.

The use of beractant in infants less than 600 g birthweight or greater than 1 750 g birthweight has not been evaluated in controlled trials. There is no controlled experience with the use of beractant in conjunction with experimental therapies for RDS (e.g., high frequency ventilation or extra-corporeal membrane oxygenation).

Contra-Indications:

There are no known contraindications to treatment with beractant.

Warnings in Clinical States:

Beractant is intended for intratracheal use only (see Dosage).

General: Usage of beractant should be restricted to a highly supervised clinical setting with immediate availability of experienced neonatologists and other clinicians experienced with intubation, ventilator management, and general care of premature infants. Vigilant clinical attention should be given to all infants prior to, during, and after administration of beractant. Infants receiving beractant should be frequently monitored with arterial or transcutaneous measurement of systemic oxygen and carbon dioxide.

Beractant can rapidly affect oxygenation and lung compliance. In some infants, hyperoxia may occur within minutes of administration of beractant. If hyperoxia develops, and transcutaneous oxygen saturation is in excess of 95%, Fi0 2 should be reduced until saturation is 90 to 95%. If the improvement in chest expansion seems excessive, peak ventilator inspiratory pressures should be immediately reduced. Failure to reduce inspiratory ventilatory pressures rapidly can result in lung overdistention and fatal pulmonary air leaks.

During the dosing procedure, transient episodes of bradycardia and decreased oxygen saturation have been reported (see Adverse Effects). If these occur, stop the dosing procedure and initiate appropriate measures to alleviate the condition. After stabilization, resume the dosing procedure.

Hyperoxia, cyanosis and reflux through the endotracheal tube, additionally to bradycardia and decreased oxygen saturation, have been the most frequently reported complications in clinical trials. If reflux occurs, drug administration should be stopped and if necessary, peak inspiratory pressure on the ventilator should be increased by 4 to 5 cm H 2O until clearing of the endotracheal tube occurs.

Increased probability of post-treatment nosocomial sepsis in beractant-treated infants was observed in clinical trials. The increased risk for sepsis among beractant-treated infants was not associated with increased mortality among these infants.

Mucous Plugs: Infants whose ventilation becomes markedly impaired during or shortly after dosing may have mucous plugging of the endotracheal tube, particularly if pulmonary secretions were prominent prior to drug administration. Suctioning of all infants prior to dosing may lessen the change of mucous plugs obstructing the endotracheal tube. If endotracheal tube obstruction from such plugs is suspected, and suctioning is unsuccessful in removing the obstruction, the blocked endotracheal tube should be replaced immediately. In the multiple-dose studies performed with beractant, there were 4 reports of endotracheal tube blockage out of 1 691 doses (0.2%).

Precautions:

General: Rales and moist breath sounds can occur transiently after administration. Endotracheal suctioning or other remedial action is necessary if clear-cut signs of airway obstruction are present.

In one of the single-dose rescue studies and one of the multi-dose prevention studies, the rate of intracranial hemorrhage was significantly higher in beractant patients than in control patients (63.3% vs 30.8%, p=0.001 and 48.8% vs 34.2%, p=0.047, respectively). However, when all controlled studies were pooled, there was no difference between treatment groups in incidences of intracranial hemorrhage.

The use of beractant in infants less than 600 g birthweight or greater than 1 750 g birthweight has not been evaluated in controlled trials. There is no controlled experience with the use of beractant in conjunction with experimental therapies for RDS (e.g., high frequency ventilation or extra-corporeal membrane oxygenation).

Carcinogenesis, Mutagenesis, Impairment of Fertility: Reproduction studies in animals have not been performed. Mutagenicity studies were negative. Carcinogenicity studies were not conducted with beractant.

Adverse Reactions:

The most commonly reported adverse experiences were associated with the dosing procedure. In the multiple-dose controlled clinical trials, each dose of beractant was divided into 4 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 above quarter-dose administration regimen to the same procedure using 2 half-doses and another 2 half-dose procedure with uninterrupted ventilation accomplished by passing the catheter through a neonatal suction valve in the endotracheal tube. 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 2 half-doses. There were no differences in these events after later doses and no differences in heart rate after any doses (see Dosage, Dosing Procedures).

The occurrence of concurrent illnesses common in premature infants was evaluated in the controlled trials.

Follow-up Evaluations: To date, no long-term complications or sequelae of beractant 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 beractant infants. Wheezing at the time of examination was more frequent among beractant infants, although there was no difference in bronchodilator therapy.

Final 12 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 beractant infants in contrast to the 6 month results. There was no difference in the incidence of cerebral palsy at 12 months.

Twenty-four month adjusted-age evaluations were completed in 429 (226 treated) of 906 surviving infants. There were significantly fewer beractant infants with rhonchi, wheezing, tachypnea or neurological findings, compared to infants treated with Sham-Air, at the time of examination. No other differences were found.

Symptoms And Treatment Of Overdose :

Overdosage with beractant has not been reported. Based on animal data, overdosage might result in acute airway obstruction. Treatment should be symptomatic and supportive.

Dosage And Administration:

For intratracheal administration only.

Beractant 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 beractant. 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 beractant. Materials are available upon request from Ross Laboratories.

No information is available on the effects of doses other than 100 mg phospholipids/kg, more than 4 doses, dosing more frequently than every 6 hours, or administration after 48 hours of age.

Each dose of beractant is 100 mg of phospholipids/kg birthweight (4 mL/kg). The Survanta Dosing Chart shows the total dosage for a range of birthweights.

Four doses of beractant can be administered in the first 48 hours of life. Doses should be given no more frequently than every 6 hours.

Directions for Use: Beractant should be inspected visually for discoloration prior to administration. The color of beractant 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 to the nature of the product.

Beractant is stored refrigerated (2 to 8°C). Before administration, beractant should be warmed by standing at room temperature for at least 20 minutes or warmed in the hand for at least 8 minutes.

Artificial warming methods should not be used. If a prevention dose is to be given, preparation of beractant should begin before the infant’s birth.

Beractant does not require reconstitution or sonication before use.

Dosing Procedures: General: Beractant is administered intratracheally. It can be instilled through a No. 5 French end-hole catheter inserted into the infant’s endotracheal tube by briefly disconnecting the endotracheal tube from the ventilator or by inserting the catheter through a neonatal suction valve without disconnecting the endotracheal tube from the ventilator or by instillation through the secondary lumen of a double lumen endotracheal tube.

If the drug is instilled through an end-hole catheter, 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. Beractant should not be instilled into a mainstem bronchus.

To ensure homogeneous distribution of beractant throughout the lungs, each dose is divided into fractional doses. Each dose can be administered in 2 half-doses or in 4 quarter-doses. Each fractional dose is administered with the infant in a different position. To administer beractant in 2 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 beractant in 4 quarter-doses, the recommended positions are: head and body inclined 5 to 10° down, head and body turned to the right; head and body inclined 5 to 10° down, head and body turned to the left; head and body inclined 5 to 10° up, head and body turned to the right; head and body inclined 5 to 10° up, head and body turned to the left (see package insert for illustrations).

The dosing procedure is facilitated if one person administers the dose while another person positions and monitors the baby.

The different methods of administering beractant were evaluated in clinical trials. In the 6 single-dose and 4 multiple-dose controlled 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 4 quarter-doses as described above.

This method of administering beractant was compared to 2 other methods in a multi-centre, randomized clinical study involving 299 infants weighing 600 g or more with RDS requiring mechanical ventilation. The other methods evaluated were: (1) 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 2 positions described above. (2) 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 2 positions described above.

There were no significant differences among the three groups in average FiO 2, a/APO 2, 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.

Administration of beractant using a double-lumen endotracheal tube is functionally equivalent to the use of the neonatal suction valve; i.e., delivery of beractant at the distal end of the endotracheal tube without interrupting mechanical ventilation. If an infant is already intubated with a single-lumen endotracheal tube, the infant should not be reintubated with a double-lumen endotracheal tube solely for the purpose of administering beractant.

First Dose: Instillation Through End-hole Catheter: Determine the total dose of beractant from the Survanta Dosing Chart based on the infant’s birthweight. Slowly withdraw the entire contents of the vial into a plastic syringe through a large gauge needle (e.g., at least 20 gauge). Do not filter beractant and avoid shaking.

Attach the premeasured No. 5 French end-hole catheter to the syringe. Fill the catheter with beractant. Discard excess beractant through the catheter so that only the total dose to be given remains in the syringe.

Before administering beractant, assure proper placement and patency of the endotracheal tube. At the discretion of the clinician, the endotracheal tube may be suctioned before administering beractant. The infant should be allowed to stabilize before proceeding with dosing.

First Fractional Dose: Prevention Strategy: Weigh, intubate and stabilize the infant. Administer the dose as soon as possible after birth, preferably within 15 minutes. Position the infant appropriately and gently inject the first quarter-dose through the catheter over 2 to 3 seconds.

After administration of the first fractional 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/minute, and sufficient positive pressure to provide adequate air exchange and chest wall excursion.

First Fractional Dose: 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 fractional dose, the infant’s ventilator settings were changed to the rate of 60/minute, inspiratory time 0.5 second, and FiO 2 1.0.

Position the infant appropriately and gently inject the first fractional dose through the catheter over 2 to 3 seconds. After administration of the first fractional dose, remove the catheter from the endotracheal tube. Return the infant to the mechanical ventilator.

Remaining Fractional Doses: Prevention and Rescue Strategies: Ventilate the infant for at least 30 seconds or until stable. Reposition the infant for instillation of the next fractional dose.

Instill the remaining fractional doses using the same procedures. After instillation of each fractional dose, remove the catheter and ventilate for at least 30 seconds or until the infant is stabilized. After instillation of the final fractional dose, remove the catheter without flushing it.

Do not suction the infant for 1 hour after dosing unless signs of significant airway obstruction occur.

After completion of the dosing procedure, resume usual ventilator management and clinical care.

Instillation Through Secondary Lumen of a Double-Lumen Endotracheal Tube: Ensure that the infant is intubated with the appropriate size double-lumen endotracheal tube. Determine the total dose of beractant from the Survanta Dosing Chart based on the infant’s birthweight. Slowly withdraw the total dose from the vial into a plastic syringe through a large-gauge needle (e.g., at least 20 gauge). Do not filter beractant and avoid shaking.

Before administering beractant, assure proper placement and patency of the endotracheal tube. At the discretion of the clinician, the endotracheal tube may be suctioned before administering beractant. The infant should be allowed to stabilize before proceeding with dosing.

First Fractional Dose: Prevention Strategy: Weigh, intubate and stabilize the infant. Administer the dose as soon as possible after birth, preferably within 15 minutes. Attach the syringe containing beractant to the secondary lumen. Position the infant appropriately and gently inject the first fractional dose through the secondary lumen over 2 to 3 seconds without interrupting ventilation. If manually ventilated, ventilate with a hand-bag with sufficient oxygen to prevent cyanosis, at a rate of 60 breaths/minute, and sufficient positive pressure to provide adequate air exchange and chest wall excursion.

First Fractional Dose: Rescue Strategy: The first dose should be given as soon as possible after the infant is placed on a ventilator for management of RDS. Immediately before instilling the first fractional dose, change the infant’s ventilator settings to the rate of 60/minute, inspiratory time 0.5 second, and FiO 2 1.0.

Position the infant appropriately and gently inject the first fractional dose through the secondary lumen over 2 to 3 seconds without interrupting mechanical ventilation.

Remaining Fractional Doses: Prevention and Rescue Strategies: Ventilate the infant for at least 30 seconds or until stable. Reposition the infant for instillation of the next fractional dose.

Instill the remaining fractional doses using the same procedures. After instillation of each fractional dose, ventilate for at least 30 seconds or until the infant is stabilized. 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.

After completion of the dosing procedure, resume usual ventilator management and clinical care.

Repeat Doses: The need for additional doses of beractant is determined by evidence of continuing respiratory distress. Dose no sooner than 6 hours after the preceding dose if the infant remains intubated and requires at least 30% inspired oxygen to maintain a PaO 2 less than or equal to 80 torr. In controlled clinical trials, 60% of patients (prevention) and 79% of patients (rescue) required more than 1 dose of beractant. 34.8% of patients (prevention) and 52.2% of patients (rescue) required 4 doses. Radiographic confirmation of RDS should be obtained before administering additional doses to those who received a prevention dose.

The dosage of beractant for each repeat dose is also 100 mg phospholipids/kg and is based on the infant’s birthweight. The infant should not be reweighed for determination of the beractant dosage. Use the Survanta Dosing Chart to determine the total dosage.

Prepare beractant and position the infant for administration of each fractional dose as previously described. After instillation of each fractional dose, remove the dosing catheter from the endotracheal tube and ventilate the infant for at least 30 seconds 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 FiO 2 was increased by 0.20 or an amount sufficient to prevent cyanosis. The ventilator delivered a rate of 30/minute with an inspiratory time less than 1.0 second. If the infant’s pretreatment rate was 30 or greater, it was left unchanged during beractant 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 beractant. Endotracheal suctioning or other remedial action is necessary if clear-cut signs of airway obstruction are present.

Availability And Storage:

Each mL of sterile, aqueous, off-white to light brown opaque, intratracheal solution, isolated from bovine lung extracts, contains: phospholipids 25 mg (200 mg phospholipids/8 mL) (including 11.0 to 15.5 mg/mL disaturated phosphatidylcholine), 0.5 to 1.75 mg/mL triglycerides; 1.4 to 3.5 mg/mL free fatty acids, and less than 1.0 mg/mL protein. May also contain sodium hydroxide and/or hydrochloric acid. It is suspended in 0.9% sodium chloride solution, and heat-sterilized. Its protein content includes 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 SPA. Preservative-free. Single glass vials of 8 mL.

Store unopened vials at refrigeration temperature (2 to 8°C). Protect from light. Store vials in carton until ready for use. Unopened, unused vials that have been warmed to room temperature may be returned to the refrigerator within 8 hours of warming, and stored for future use. Drug should not be warmed and returned to the refrigerator more than once. Each single use vial should be entered with a needle only once. Used vials with residual drug should be discarded.

SURVANTA® Abbott Beractant Lung Surfactant

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