Beractant

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

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 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.

Beractant is a lung surface acting agent, or "surfactant." It helps the lungs function normally. Beractant is similar to the natural fluid in the lungs that helps maintain effective breathing.

Beractant is used to treat or prevent respiratory distress syndrome (RDS) in a premature baby whose lungs have not fully developed.

Beractant may also be used for purposes not listed in this medication guide.

No pharmacokinetic studies in humans.1

Absorption

Onset

Marked improvements in oxygenation occur within minutes of administration.1 2

Duration

Improvements in arterial-alveolar oxygen ratio (a/APO2), FiO2, and mean airway pressure (MAP) sustained for 48–72 hours following administration.1

Storage

Intratracheal

2–8° C in carton.1 Protect from light.1 Usual color of commercially available suspension is off-white to light brown.1

Prior to use, warm at room temperature for up to 24 hours (see Intratracheal Administration under Dosage and Administration); record date and time whenever vial is removed from refrigerator.1

May return unopened, unused vials to refrigerator within 24 hours of warming.1 Do not warm and return to refrigeration more than once.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Respiratory distress treatment: Premature neonates: Limited data available in premature neonates <600 g or >1,750 g:

Prophylactic therapy: Endotracheal: 4 mL/kg (100 mg phospholipids/kg) as soon as possible after birth, preferably within 15 minutes; as many as 4 doses may be administered during the first 48 hours of life, no more frequently than 6 hours apart; usually requires no more frequent dosing than every 12 hours unless surfactant is being inactivated by an infectious process, meconium, or blood (AAP [Polin 2014]). The need for additional doses is determined by evidence of continuing respiratory distress; if the neonate is still intubated and requiring at least 30% inspired oxygen to maintain a PaO2 ≤80 torr. Note: For newborns who do not require mechanical ventilation for severe RDS, current guidelines recommend using CPAP immediately after birth with subsequent selective surfactant administration (AAP [Polin 2014]).

Rescue treatment: Endotracheal: 4 mL/kg (100 mg phospholipids/kg) as soon as the diagnosis of RDS is made; may repeat if needed, no more frequently than every 6 hours to a maximum of 4 doses during the first 48 hours of life; usually requires no more frequent dosing than every 12 hours unless surfactant is being inactivated by an infectious process, meconium, or blood (AAP [Polin 2014]). The need for additional doses is determined by evidence of continuing respiratory distress or if the neonate is still intubated and requiring at least 30% inspired oxygen to maintain a PaO2 ≤80 torr.

Store intact vials in refrigerator between 2°C and 8°C (35.6°F and 46.4°F); protect from light and store vials in original carton until ready for use. Unopened, unused vials that have been warmed to room temperature may be returned to the refrigerator within 24 hours of warming and stored for future use. Do not remove vial from the refrigerator for >24 hours; do not warm and return to refrigerator more than once.

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Concerns related to adverse effects:

• Mucous plugs: Marked impairment of ventilation during or shortly after dosing may indicate mucous plugging of the endotracheal tube; suctioning all neonates prior to administration may decrease chance of endotracheal tube obstruction. Replace endotracheal tube immediately if obstruction is not removed with suctioning.

• Nosocomial sepsis: There is an increased risk of post-treatment nosocomial sepsis in treated neonates this increased risk was not associated with increased mortality.

• Transient adverse effects: Transient episodes of bradycardia and decreased oxygen saturation may occur. Discontinue dosing procedure and initiate measures to alleviate the condition; may reinstitute after the patient is stable. Rales and moist breath sounds may occur; endotracheal suctioning or other remedial action is necessary if clear-cut signs of airway obstruction are present.

Other warnings/precautions:

• Administration: Intended for endotracheal administration only.

• Appropriate use: Use in neonates <600 grams birth weight or >1,750 grams birth weight has not been evaluated.

• Lung oxygenation/lung compliance: Produces rapid improvements in lung oxygenation and compliance that may require frequent adjustments to oxygen delivery and ventilator settings; hyperoxia may occur within minutes of administration.

• Trained personnel: Rapidly affects oxygenation and lung compliance; restrict use to a highly-supervised clinical setting with immediate availability of clinicians experienced in intubation and ventilatory management of premature neonates.

Data not available

Clinical effects of SURVANTA were demonstrated in six single-dose and four multiple-dose randomized, multicenter, 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 600-1250 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 FiO 2 >/=0.30. Results of the studies at 28 days of age are shown in Table 1.

Rescue Studies

Infants of 600-1750 g birth weight with RDS requiring mechanical ventilation and an FiO 2 >/=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 FiO 2 >/=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/APO 2 ), FiO 2 , 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, FiO 2 improved significantly.

General

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 age.

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/m 2 /day) was administered subcutaneously to newborn rats for 5 days. The rats reproduced normally and there were no observable adverse effects in their offspring.