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(beractant)intratracheal suspensionSterile SuspensionFor Intratracheal Administration Only
SURVANTA ® (beractant)
Intratracheal Suspension is a sterile, non-pyrogenic 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 25 mg/mL phospholipids (including
11.0-15.5 mg/mL disaturated phosphatidylcholine), 0.5-1.75 mg/mL triglycerides,
1.4-3.5 mg/mL free fatty acids, and less than 1.0 mg/mL protein.
It is 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.Each mL of SURVANTA contains 25 mg of phospholipids.
It is an off-white to light brown liquid supplied in single-use glass
vials containing 4 mL (100 mg phospholipids) or 8 mL (200 mg phospholipids).
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.
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.
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-labelled 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.
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.
Infants of 600-1250 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 6 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.Table 1.Study 1 SURVANTAControlP-ValueNumber infants studied119124 Incidence of RDS (%)27.663.5< 0.001Death due to RDS (%)2.519.5< 0.001Death or BPD due to RDS (%)48.752.80.536Death due to any cause (%)7.622.80.001Air Leaksa (%)5.921.70.001Pulmonary interstitial emphysema (%)20.840.00.001Study 2b SURVANTAControlP-ValueNumber infants studied9196 Incidence of RDS (%)28.648.30.007Death due to RDS (%)1.110.50.006Death or BPD due to RDS (%)27.544.20.018Death due to any cause C(%)16.513.70.633Air Leaks a(%)14.519.60.374Pulmonary interstitial emphysema (%)26.533.20.298aPneumothorax or pneumopericardiumbStudy discontinued when Treatment IND initiatedcNo cause of death in the SURVANTA group was significantly increased; the higher number of deaths in this group was due to the sum of all causes.
Infants of 600-1750 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 8 hours of age. Infants could receive up to three additional
doses in the first 48 hours, as often as every 6 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.Table 2.Study 3a SURVANTAControlP-ValueNumber infants studied198193 Death due to RDS (%)11.618.10.071Death or BPD due to RDS (%)18.104.22.168Death due to any cause (%)21.726.40.285Air Leaksb (%)11.829.5<0.001Pulmonary interstitial emphysema (%)16.334.0<0.001Study 4 SURVANTAControlP-ValueNumber infants studied204203 Death due to RDS (%)6.422.3< 0.001Death or BPD due to RDS (%)43.663.4< 0.001Death due to any cause (%)15.228.20.001Air Leaksb (%)11.222.20.005Pulmonary interstitial emphysema (%)20.844.4< 0.001aStudy discontinued when
Treatment IND initiatedbPneumothorax
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 48-72 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.
Indications And Usage
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.
In premature infants less than 1250 g birth
weight or with evidence of surfactant deficiency, give SURVANTA as
soon as possible, preferably within 15 minutes of birth.
To treat infants with RDS confirmed by x-ray
and requiring mechanical ventilation, give SURVANTA as soon as possible,
preferably by 8 hours of age.
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.
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 (Table 3). 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 weight has not been evaluated in controlled
trials. There is no controlled experience with 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 100 mg phospholipids/kg, more than four doses, dosing more
frequently than every 6 hours, or administration after 48 hours of
- SURVANTA is administered intratracheally
- By instillation through a 5 French end-hole catheter. The catheter
- Can be inserted into the infant’s endotracheal tube without interrupting
- Ventilation by passing the catheter through a neonatal suction valve
- Attached to the endotracheal tube. Alternatively, SURVANTA can be
- Instilled through the catheter by briefly disconnecting the endotracheal
- Tube from the ventilator.The
- Neonatal suction valve used for administering SURVANTA should be a
- Type that allows entry of the catheter into the endotracheal tube
- Without interrupting ventilation and also maintains a closed airway
- Circuit system by sealing the valve around the catheter.If the neonatal suction valve is used, the
- Catheter should be rigid enough to pass easily into the endotracheal
- Tube. A very soft and pliable catheter may twist or curl within the
- Neonatal suction valve. The length of the catheter should be shortened
- So that the tip of the catheter protrudes just beyond the end of the
- Endotracheal tube above the infant’s carina. SURVANTA should not be
- Instilled into a mainstem bronchus.To ensure homogenous distribution of SURVANTA throughout the lungs,
- Each dose is divided into four quarter-doses.Each quarter-dose is administered with the
- Infant in a different position. The recommended positions are:Head and body inclined 5-10° down, head turned to the rightHead and body inclined 5-10° down, head turned to the leftHead and body inclined 5-10° up, head turned to the rightHead and body inclined 5-10° up, head turned to the leftThe dosing procedure is facilitated
- If one person administers the dose while another person positions
- And monitors the infant.
Impairment Of Fertility
Carcinogenicity studies have not been performed with SURVANTA. SURVANTA
was negative when tested in the Ames test for mutagenicity. Using
the maximum feasible dose volume, SURVANTA up to 500 mg phospholipids/kg/day
(approximately one-third the premature infant dose based on mg/m2/day) was administered subcutaneously to newborn rats
for 5 days. The rats reproduced normally and there were no observable
adverse effects in their offspring.
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 which were
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.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.Table 3.All Controlled
StudiesConcurrent EventSURVANTA (%)Control (%)P-ValueaPatent ductus arteriosus46.947.10.814Intracranial hemorrhage22.214.171.124Severe intracranial hemorrhage126.96.36.1993Pulmonary air leaks10.924.7< 0.001Pulmonary interstitial emphysema20.238.4< 0.001Necrotizing enterocolitis188.8.131.527Apnea65.459.60.283Severe apnea184.108.40.206Post-treatment sepsis20.716.10.019Post-treatment infection10.29.10.345Pulmonary hemorrhage220.127.116.11aP-value
comparing groups in controlled studies 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% v 30.8%, P = 0.001; and 48.8% v 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 pretreatment 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
Lung consolidation, blood from the endotracheal
tube, deterioration after weaning, respiratory decompensation, subglottic
stenosis, paralyzed diaphragm, respiratory failure.
Hypotension, hypertension, tachycardia,
ventricular tachycardia, aortic thrombosis, cardiac failure, cardio-respiratory
arrest, increased apical pulse, persistent fetal circulation, air
embolism, total anomalous pulmonary venous return.
Abdominal distention, hemorrhage, intestinal
perforations, volvulus, bowel infarct, feeding intolerance, hepatic
failure, stress ulcer.
Renal failure, hematuria.
Coagulopathy, thrombocytopenia, disseminated
Central Nervous System
Adrenal hemorrhage, inappropriate ADH secretion,
To date, no long-term complications or sequelae
of SURVANTA therapy have been found.
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.
Six-month adjusted age follow-up evaluations
have been completed in 631 (345 treated) of 916 surviving infants.
There were significantly less cerebral palsy and need for supplemental
oxygen in SURVANTA infants than controls. Wheezing at the time of
examination was significantly 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
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.
Dosage And Administration
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. Materials are available upon request from AbbVie Inc.
Each dose of SURVANTA is 100 mg of phospholipids/kg
birth weight (4 mL/kg). The SURVANTA Dosing Chart shows the total
dosage for a range of birth weights.SURVANTA DOSING
CHART Weight (grams) Total Dose (mL) Weight (grams) Total Dose (mL) 600-6502.61301-13505.4651-7002.81351-14005.6701-7503.01401-14505.8751-8003.21451-15006.0801-8503.41501-15506.2851-9003.61551-16006.4901-9503.81601-16506.6951-10004.01651-17006.81001-10504.21701-17507.01051-11004.41751-18007.21101-11504.61801-18507.41151-12004.81851-19007.61201-12505.01901-19507.81251-13005.21951-20008.0Four doses of SURVANTA can be administered
in the first 48 hours of life. Doses should be given no more frequently
than every 6 hours.
Directions For Use
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 the product.SURVANTA is stored refrigerated (2-8°C). Date and time need to be recorded in the box on front of the carton or vial, whenever SURVANTA is removed from the refrigerator. Before administration, SURVANTA 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 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 REMOVED FROM THE REFRIGERATOR FOR MORE THAN 24 HOURS. 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.
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 minutes.
Position the infant appropriately and gently inject the first quarter-dose
through the catheter over 2-3 seconds.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/minute, 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/minute, inspiratory time 0.5 second, and FiO2 1.0.Position the
infant appropriately and gently inject the first quarter-dose through
the catheter over 2-3 seconds. After administration of the first
quarter-dose, remove the catheter from the endotracheal tube and continue
mechanical ventilation.In both
strategies, ventilate the infant for at least 30 seconds 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 least30 seconds 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 hour after dosing unless
signs of significant airway obstruction occur.After completion of the dosing procedure, resume usual
ventilator management and clinical care.
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
SURVANTA dosage. Use the SURVANTA Dosing Chart to determine the total
dosage.The need for additional
doses of SURVANTA 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 hours after the preceding dose if the infant
remains intubated and requires at least 30% inspired oxygen to maintain
a PaO2 less than or equal to 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 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 FiO2 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 than1.0 second. If the infant’s pretreatment
rate was 30 or greater, 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.
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.
SURVANTA (beractant) Intratracheal Suspension is supplied in single-use glass vials containing 4 mL (NDC 0074-1040-04) or 8 mL of SURVANTA (NDC 0074-1040-08). Each milliliter contains 25 mg of phospholipids suspended in 0.9% sodium chloride solution. The color is off-white to light brown.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.LITHO IN USAAbbVie Inc.North Chicago, IL 60064, U.S.A.03-A683 December, 2012
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