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.

Prevention:

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.

Rescue:

To treat infants with RDS confirmed by x-ray and requiring mechanical ventilation, give SURVANTA as soon as possible, preferably by eight hours 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. Materials are available upon request.

Dosage:

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:

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.

Dosing Procedures

General

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 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 dosing procedure is facilitated if one 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 (e.g., at least 20 gauge). Do Not Filter SURVANTA And Avoid Shaking.

Attach the pre-measured 5 French end-hole catheter to the syringe. Fill the catheter with SURVANTA. Discard excess SURVANTA 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.

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 then gently inject the first fractional dose through the catheter over two to three 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 fractional dose through the catheter over two to three seconds. After administration of the first fractional 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 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 least 30 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 one hour 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 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 six 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 than 1.0 second. If the infant's pre-treatment 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.

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

Carcinogenesis, Mutagenesis, 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.

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 weights has not been evaluated in controlled trials. There is no controlled experience with 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.

Not Applicable

Not Applicable

Not Applicable

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, cardio-respiratory 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 ADH secretion, hyperphosphatemia.

Musculoskeletal

Inguinal hernia.

Systemic

fever, deterioration

Pediatric population

Summary of the safety profile:

Intracranial haemorrhage has been observed in patients who received either Beractant or placebo. The incidence of intracranial haemorrhage in all patients is similar to that reported in the literature in this patient population. Pulmonary haemorrhage has also been reported. Blockage of the endotracheal tube by mucous secretions has been reported. No other serious adverse reactions have been reported.

These are presented in the following table:

The following frequency categories are used: Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100).

No antibody production to Survanta proteins has been observed.

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 less 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 2.

Table 2 : All Controlled Studies:

 * P-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% 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 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.

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, 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 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 found.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

− The National Pharmacovigilance and Drug Safety Centre (NPC)

·         Fax: +966-11-205-7662

·         Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

·         Toll free phone: 8002490000

·         E-mail: npc.drug@sfda.gov.sa

·         Website: www.sfda.gov.sa/npc

Overdose with SURVANTA has not been reported. Based on animal data, overdose 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 overdose. Endotracheal suctioning or other remedial action is not required unless clear-cut signs of airway obstruction are present.

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).

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.

Pharmacologic Properties

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.

Activity

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.

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 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.

Description Of Clinical Studies

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.

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.

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.

Survanta Intratracheal Suspension is supplied in single-use glass vials containing 4 mL or 8 mL of Survanta.

Each milliliter contains 25 mg of phospholipids suspended in 0.9% sodium chloride solution. The color is off-white to light brown.

Not applicable.

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.

SURVANTA should be inspected visually for discoloration prior to administration. The color of SURVANTA is off-white to light brown.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.