Survanta
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Survanta - Scientific Information

Manufacture: AbbVie
Country: Canada
Condition: Respiratory Distress Syndrome
Class: Lung surfactants
Form: Syrup
Ingredients: beractant, proteins, sodium chloride

Pharmaceutical Information

Drug Substance

Trade name:SURVANTA
Generic name:Beractant
Chemical name:None
Other names:Surfactant TA
Molecular formula and molecular mass:Not applicable
Structural formula:Not applicable
Physicochemical properties:Not applicable
Description:A natural product isolated from bovine lung extracts (Bovine Lung Lipids) containing phospholipids, neutral lipids, fatty acids and protein. It is fortified by the addition of the synthetic lipids, namely dipalmitoyl-phosphotidylcholine (colfosceril palmitate), palmitic acid and tripalmitin (fortification lipids). It is formulated as a sterile, aqueous liquid for intratracheal instillation.
Physical description:Off-white to light brown opaque.

Clinical Trials

Study Demographics and Trial Design

Clinical effects of SURVANTA (beractant, intratracheal suspension) 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.

The studies were of two basic designs: treatment or rescue studies in which surfactant was given to low birthweight infants with established RDS, and prevention studies in which surfactant was given shortly after birth to infants at highest risk for RDS.

Table 1 Summary of Patient Demographics for Clinical Trials in Prevention (Prophylaxis) and Treatment (Rescue) of Respiratory Distress Syndrome (RDS/Hyaline Membrane Disease) in Premature Infants
Study #Trial DesignDosage, Route of Administration and DurationStudy Subjects (n)Mean Gestational Age (weeks)Gender (% Male / Female)
Prevention StudiesStudy 1Randomised, multicenter, double blind, placebo-controlled studyBeractant, intratracheal suspension
100 mg phospholipids/kg birth weight within 15 minutes of birth. Infants could receive three additional doses in the first 48 hours.
SURVANTA11926.652/48
Placebo (Sham Air)12426.648/52
Study 2*Randomised, multicenter, double blind, placebo-controlled studyBeractant, intratracheal suspension
100 mg phospholipids/kg birth weight within 15 minutes of birth. Infants could receive three additional doses in the first 48 hours.
SURVANTA9126.560/40
Placebo (Sham Air)9626.859/41
Rescue StudiesStudy 3*Randomised, multicenter, double blind, placebo-controlled studyBeractant, intratracheal suspension
100 mg phospholipids/kg birth weight within 8 hours of birth. Infants could receive three additional doses in the first 48 hours.
SURVANTA19827.861/39
Placebo (Sham Air)19327.651/49
Study 4Randomised, multicenter, double blind, placebo-controlled studyBeractant, intratracheal suspension
100 mg phospholipids/kg birth weight within 8 hours of birth. Infants could receive three additional doses in the first 48 hours.
SURVANTA20427.557/43
Placebo (Sham Air)20327.458/42

* Study discontinued when Treatment IND initiated

Study Results

Prevention Studies

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 Studies 1 and 2 at 28 days of age are shown in Table 2.

Table 2 Results of Prevention Studies
Study 1Study 2a
SURVANTA
(n=119)
Control
(n=124)
P-ValueSURVANTA
(n=91)
Control
(n=96)
P-Value
Incidence of RDS (%)27.663.5<0.00128.648.30.007
Death due to RDS (%)2.519.5<0.0011.110.50.006
Death or BPD due to RDS (%)48.752.80.53627.544.20.018
Death due to any cause (%)7.622.80.00116.5b13.70.633
Air Leaksc (%)5.921.70.00114.519.60.374
Pulmonary interstitial emphysema (%)20.840.00.00126.533.20.298

a Study discontinued when Treatment IND initiated

b No 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.

c Pneumothorax or pneumopericardium

Rescue Studies

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 Studies 3 and 4 at 28 days of age are shown in Table 3.

Table 3 Results of Rescue Studies
Study 3aStudy 4
SURVANTA
(n=198)
Control
(n=193)
P-ValueSURVANTA
(n=204)
Control
(n=203)
P-Value
Death due to RDS (%)11.618.10.0716.422.3<0.001
Death or BPD due to RDS (%)59.166.80.10243.663.4<0.001
Death due to any cause (%)21.726.40.28515.228.20.001
Air Leaksb (%)11.829.5<0.00111.222.20.005
Pulmonary interstitial emphysema (%)16.334.0<0.00120.844.4<0.001

a Study discontinued when Treatment IND initiated

b Pneumothorax or pneumopericardium

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.

Detailed Pharmacology

In vitro, SURVANTA (beractant, intratracheal suspension) 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 doses of SURVANTA improve lung pressure-volume measurements, lung compliance, and oxygenation in premature rabbits and sheep.

Surface-tension lowering cannot be directly measured in vivo. To assess the nonclinical activity at several doses of SURVANTA, indicators of pulmonary function were measured in animals: arterial blood gases, pulmonary compliance, and lung pressure-volume curves.

Human Pharmacology

Clinical dose-response studies were not done with SURVANTA. The clinical dose of 100 mg phospholipids/kg/dose was selected because previous experience with the same dose of the lyophilized powder formulation of Surfactant TA demonstrated its acute efficacy and safety.

Animal Pharmacology

Activity Studies

Table 4 summarizes relevant aspects of experimental design and results of the animal experiments with SURVANTA and Surfactant TA, a biochemically equivalent powder formulation of SURVANTA. The studies are presented in order of increasing maturity of the animals.

All studies reported in Table 4 were single-dose studies, because early deaths of premature animals hamper the ability to study responses to multiple-doses of surfactant in surfactant-deficient animals.

Table 4 Animal Activity Studies
Study IdentifierDrugAnimal (N)DoseMeasure of ResponseResults
A-1SURVANTA27-day rabbits
59 treated
15 mg/kg,
30 mg/kg,
50 mg/kg,
100 mg/kg at birth & after 15 & 30 minutes of ventilation
1) compliance
2) pressure-volume curves
1) 100 mg/kg: increased compliance at all times (P<0.05)
50 mg/kg: increased compliance only with dose at birth (P<0.05)
2) Treatment at birth: 30, 50, 100 mg/kg: increased volume (P=0.05); 15 mg/kg: no effect
Treatment at 30 minutes: no effect
A-2Surfactant TA27-day rabbits
30 treated
26 control
75 mg/kg1) PIP
2) tidal volume
3) compliance
1) decreased PIP (P<0.005)
2) no difference
3) increased compliance (P<0.005)
A-3Surfactant TA27-day rabbits
7 treated
75 mg/kgcomplianceIncreased compliance (P<0.01)
A-4SURVANTA (SUR)
Calf lung surfactant (CSA)
Rabbit surfactant (RSA)
No control
28-day rabbits
SUR = 38
CSA = 32
RSA = 34
75 mg/kgPIP, compliance, terminal pH, pCO2No difference between the three surfactants
A-5Surfactant TA (STA)
Sheep surfactant (SSA)
Rabbit surfactant (RSA)
Human surfactant (HSA)
120-122-day lambs
STA = 5
SSA = 5
RSA = 5
HSA = 7
Control = 5
50 mg/kg1) PIP
2) ventilation efficiency index (VEI)
3) tidal volume
4) compliance
1) STA not different than control
2) SSA > HSA, STA (P<0.05) STA, SSA, RSA, HSA > control (P<0.01)
A-6SURVANTA (SUR)
Sheep surfactant (SSA)
132-day lambs
SUR = 5
SSA = 5
Control = 7
100 mg/kgPIP, pO2, pCO2, FiO2, complianceControl animals sacrificed at 5 hours due to terminal respiratory failurre
Treated animals survived to 24 hours: no difference between SUR and SSA
A-7Surfactant TA130-147-day premature baboons
10 treated
5 control
100 mg/kg1) a/APO2, FiO2, MAP
2) compliance
3) pressure-volume curve
1) At 16 hours, decreased a/APO2, increased FiO2, MAP (P<0.005)
2) Increased compliance (P<0.005)
3) Increased volume at all pressures (P<0.001)

Metabolic Studies

Lung clearance behaviour of SURVANTA was also investigated in some of the experiments above using radiolabeled lipid components. SURVANTA clearance occurs in two phases: initial clearance from the airspaces and subsequent clearance from the lungs.

  1. Premature Animals

    In preterm rabbits, airspace clearance of SURVANTA with labeled phosphatidylcholine showed that, by six hours, 45 to 60% of the labeled lipid was cleared from the alveoli to become lung-associated. At six hours, there was essentially no loss of the SURVANTA lipid from the total lung.

    In preterm sheep, SURVANTA was cleared equivalently from the airspaces with only about 20% of the treatment dose recovered in alveolar washes at 24 hours. However, as in preterm rabbits, there was little or no clearance of SURVANTA from the lungs.

  2. Three-Day-Old Rabbits

    Older animals offer the opportunity to study surfactant clearance over longer periods of time than is possible in premature animals. The clearance of labeled SURVANTA components in full-term, three-day-old rabbits and in adult animals was examined in a study.

    SURVANTA with 14C-choline-labeled phosphatidylcholine was given intratracheally to 3-day old rabbits.

    After a dose of 100 mg/kg, there was about 22% clearance of the label from the total lung over 24 hours. About 45% of the tracheally-injected label was recovered in alveolar wash at 24 hours.

  3. Adult Rabbits

    SURVANTA with labeled phosphatidylcholine was given to adult rabbits. After tracheal injection of approximately 90 mg/kg SURVANTA, the labeled phospha-tidylcholine was rapidly lost from the alveolar wash, with 10% recovered at 24 hours. About 55% of the label was recovered in the total lung at 24 hours. These data confirm earlier work with natural surfactants that showed different clearance behaviour in adult animals.

Distribution

A clearance study performed on 27-day premature rabbits, also examined the distribution of SURVANTA in the animals' lungs. In order to measure the distribution of the SURVANTA, rabbits were treated at birth or 30 minutes after the onset of ventilation with 50 mg/kg of SURVANTA radiolabeled with 14C-dipalmitoylphosphatidylcholine.

Following sacrifice the lungs were removed, frozen over dry ice, and sectioned into 80 pieces. 14C radioactivity was then counted in the lipid extracts of the lung pieces and normalized by the protein contents of the lung pieces and by the number of counts that would have been received had the distribution been totally uniform.

Rabbits given surfactant after 30 minutes of ventilation had increased percentages of lung pieces that received <20%, 20 to 40%, and >200% the expected dose, indicating a non-uniform surfactant distribution after a period of ventilation.

Toxicology

Acute Toxicity Studies

SURVANTA (beractant, intratracheal suspension) was evaluated for acute intratracheal toxicity in mice and rats, for subchronic intratracheal toxicity in rats and ferrets, and for sensitization potential in guinea pigs. Two acute toxicity studies are summarized in Table 5.

The only acute toxicity observed in preclinical studies was dyspnea, and, in extreme cases, death from asphyxiation. These findings occurred in saline-treated control animals as well as in SURVANTA–treated animals.

Subacute Toxicity Studies

One rat and three ferrets multidose, subacute toxicity studies were conducted with SURVANTA. Ferrets were chosen as a non-rodent model because their pulmonary structure resembles that of man. The four subacute toxicity studies are summarized in Table 6 to 9.

Carcinogenicity Studies

Carcinogenicity studies have not been performed with SURVANTA.

Mutagenicity Studies

Mutagenicity studies were negative.

Reproduction and Teratology Studies

Beractant 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 five days. These rats reproduced normally and there were no observable adverse effects in their offspring.

Special Studies

A special toxicity study was undertaken to determine the antigenicity of SURVANTA. A group of 10 adult male guinea pigs was administered three doses of SURVANTA intraperitoneally on alternate days followed three weeks later by a single intratracheal challenge dose. Two positive control groups were administered sensitization and challenge doses of egg albumin according to the same schedule and routes of administration for the group administered SURVANTA. Cyanosis, dyspnea, unsteady gait, ataxia, convulsions and deaths were observed in both egg-albumin-treated groups, but no such manifestations of anaphylaxis were seen in the group administered SURVANTA.

Table 5 Acute Toxicity Studies of SURVANTA
Species/ Study No.SexAge (weeks)Route of AdministrationDose RangeVehicleSignsLethalityTime of Death
mg/kgamL/kg
Mouse
T84-296
Maleb5Intratracheal16040.9% salineRalesNo deathsc--
Rat
T84-296
Maleb5Intratracheal16040.9% salineRalesNo deaths--
T85-287Male5Intratracheal10040.9% salineMinimal inflammatory response in both groups. Minimal pulmonary inflammatory reactions plus minimal to mild intra-alveolar microgranulomata; still present 7 days after treatmentNo deaths--

a mg phospholipid/kg body weight

b This study was conducted as exploratory research; not all GLP requirements were met. Lyophilized Surfactant TA.

c One of ten mice died 12 days after treatment but the death was not considered treatment-related.

Table 6 Two-Week Toxicity Study of Surfactant TA (Abbott-60386X) Administered Intratracheally to Young Rats
GroupT0T1T2T3T4
Dosage (mg phospholipid/kg/day)0
(sham-treated)
0
(0.9% saline)
100100
(every other day)
200
(100 b.i.d.)
Dose Volume
(mL/kg)
---4448
(4 b.i.d.)
No. Deaths / No. Treated0/101/10*1/11*2/10*6/13*
Body Weight Gain75%63%66%70%57%
Toxic SignsDyspnea (attributed to intratracheal catheter)Acute respiratory distress immediately after treatment (attributed to transient airway obstruction by saline or test surfactant)
Hematology---Bone marrow M:E ratios of saline- and surfactant-treated rats slightly higher than values for sham-treated rats
Clinical Chemistry---No biologically-meaningful differences from values for sham-treated rats
Organ Heights---No abnormalitiesIncreased absolute or relative lung weights
Anatomic PathologyInterstitial pneumonia without granulomatous changes in 2/10 sham-treated and 10/10 saline-treated ratsPulmonary changes characterized by granulomatous pneumonia with fat-positive material in 30/30 surfactant-treated rats (consistent with treatment route and lipoid nature of surfactant)

* Deaths were attributed to mechanical suffocation, not surfactant toxicity.

Table 7 Three-Day Multiple-Dose Intratracheal Toxicity Study of SURVANTA in Young Ferrets (With One-Month Recovery Period)
GroupT0T1T2
Dosage (mg phospholipid/kg/day)0
(0.9% saline)
100300
Dose Volume
(mL/kg, q.i.d.)
12412
No. Deaths / No. Treated0/120/120/12
Body Weight M
Gain F
5.2%
6.5%
5.7%
2.9%
5.0%
2.1%
Toxic SignsOccasional gasping or licking during treatmentOccasional gasping or licking in both groups. Infrequent episodes of ataxia or prostration in high-dosage group attributed to transient airway obstruction
Hematology--No toxicologically-meaningful differences from controls
Clinical Chemistry--No toxicologically-meaningful differences from controls
Organ Weights--Dose-related increased lung weights
Anatomic PathologyNoneMild inflammatory changes in the lungs at the end of the 3-day treatment period and after a 1-month recovery period
Table 8 Ten-Day Toxicity Study of SURVANTA (Abbott-60386X) Administered Intratracheally to Weanling Ferrets
GroupT0T1T2T3
Dosage (mg phospholipid/kg/day)0
(sham-treated)
0
(0.9% saline)
100100
Dose Volume (mL/kg)---848
No. Deaths/
No. Treated
0/80/80/80/8
Body Weight Gain24%24%22%21%
Toxic SignsNoneDyspnea immediately after treatment (attributed to transient airway obstruction by saline or test surfactant)
Hematology--No statistically significant differences from values for sham-treated ferrets
Clinical Chemistry--No statistically significant differences from values for sham-treated ferrets
Organ Weights--No statistically significant differences from values for sham-treated ferrets
Anatomic PathologyNoneNoneSparsely-distributed, minimal to mild, pulmonary microgranulomata in 16/16 surfactant-treated ferrets (consistent with treatment route and lipoid nature of test surfactant)
Table 9 One-Month Intratracheal Toxicity Study of SURVANTA in Young Ferrets
GroupT0T1T2
Dosage (mg phospholipid/kg/day)0
(0.9% saline)
300300, b.i.d.
Dose Volume (mL/kg, q.i.d.)12, b.i.d.1212, b.i.d.
No. Deaths / No. Treated0/101/10*1/10*
Body Weight M
Gain F
64.6%
44.0%
62.7%
44.7%
46.4%
27.5%
Toxic SignsOccasional gasping during treatmentOccasional gasping during treatment and infrequent episodes of prostration attributed to transient airway obstruction
Hematology--No toxicologically-meaningful differences from controls
Clinical Chemistry--No toxicologically-meaningful differences from controls
Organ Weights--Increased lung weights
Anatomic PathologyNoneScattered pneumonic infiltrates in lung parenchyma of nearly all SURVANTA-treated ferrets; most severe in high-dosage group

* Deaths were attributed to mechanical suffocation.