Beractant

INDICATIONS AND USAGE SURVANTA is indicated for prevention and treatment (“rescue”) of Respiratory Distress Syndrome (RDS) (hyaline membrane disease) in premature infants.

CLINICAL PHARMACOLOGY 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. 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.

DOSAGE AND ADMINISTRATION 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 administration of SURVANTA is facilitated if one person administers the dose while another person positions and monitors the infant. 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. Administer SURVANTA intratracheally by instillation through a 5 French end-hole catheter. Recommended Dosage Each dose of SURVANTA is 100 mg of phospholipids/kg birth weight (4 mL/kg). In the prevention strategy, in premature infants with evidence of surfactant deficiency, give the first dose of SURVANTA as soon as possible, preferably within 15 minutes of birth. To treat infants with RDS confirmed by radiographic and clinical findings, give the first dose of SURVANTA as soon as possible, preferably by 8 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 6 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 color 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 (36°F to 46°F [2°C to 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-dose 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. Administration For endotracheal administration using a 5 French end-hole catheter: 1. Slowly withdraw the entire contents of the vial into a plastic syringe through a large-gauge needle (e.g., at least 20 gauge). 2. 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. 3. When administering SURVANTA using a 5 French end-hole catheter, administer in four quarter-dose aliquots. Each quarter-dose is administered with the infant in a different position: 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 4. First quarter-dose aliquot of SURVANTA suspension: a. Position the infant appropriately in one of the four recommended positions. b. Insert the 5-French end-hole catheter into the endotracheal tube. The tip of

ADVERSE REACTIONS 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 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 Studies Concurrent Event SURVANTA (%) Control (%) P -Value a Patent ductus arteriosus 46.9 47.1 0.814 Intracranial hemorrhage 48.1 45.2 0.241 Severe intracranial hemorrhage 24.1 23.3 0.693 Pulmonary air leaks 10.9 24.7 < 0.001 Pulmonary interstitial emphysema 20.2 38.4 < 0.001 Necrotizing enterocolitis 6.1 5.3 0.427 Apnea 65.4 59.6 0.283 Severe apnea 46.1 42.5 0.114 Post-treatment sepsis 20.7 16.1 0.019 Post-treatment infection 10.2 9.1 0.345 Pulmonary hemorrhage 7.2 5.3 0.166 a 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% 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 to SURVANTA. 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. 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 mani

WARNINGS SURVANTA can rapidly affect oxygenation and lung compliance within minutes of administration of SURVANTA. 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.

CONTRAINDICATIONS None

OVERDOSAGE 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.