CALFACTANT: 41 Adverse Event Reports & Safety Profile

Calfactant is an extract of natural bovine lung (pulmonary) surfactant consisting of 85% phospholipids, 8% neutral lipids, and 7% hydrophobic surfactant-associated proteins B and C (SP-B and SP-C). The molecular weight of SP-B is 8.7 kDa and the molecular weight of SP-C is 3.7 kDa. INFASURF (calfactant) intratracheal suspension is a sterile, off-white suspension for intratracheal use. INFASURF contains calfactant at a concentration of 35 mg/mL in either a 105 mg/3 mL or 210 mg/6 mL single-dose vial. Each milliliter of INFASURF contains 35 mg of phospholipids and 0.7 mg of surface-associated proteins of which 0.26 mg is SP-B, a 79-amino acid protein, and 0.44 mg is SP-C, a 35-amino acid peptide. The amount of phospholipids is calculated from the content of phosphorous and contains 26 mg of phosphatidylcholine of which 16 mg is disaturated phosphatidylcholine. It is suspended in 0.9% Sodium Chloride Irrigation, USP. The pH is approximately 5.0 - 6.2 (target pH 5.7). INFASURF contains no preservatives.

AND USAGE INFASURF is indicated: to reduce the risk of respiratory distress syndrome (RDS) in preterm neonates <29 weeks of gestational age at risk for RDS. for the rescue treatment of RDS in preterm neonates ≤72 hours of age with RDS who require endotracheal intubation. INFASURF ® is a surfactant indicated: to reduce the risk of respiratory distress syndrome (RDS) in preterm neonates < 29 weeks gestational age at risk for RDS. (1) for the rescue treatment of preterm neonates ≤72 hours of age with RDS who require endotracheal intubation. (1)

AND ADMINISTRATION

2.1 Recommended Dosage The recommended dose of INFASURF is 3 mL/kg body weight at birth administered intratracheally through an endotracheal tube. INFASURF can be administered every 12 hours for a total of up to three doses. To reduce the risk of RDS in preterm neonates &lt;29 weeks of gestational age at risk for RDS, administer INFASURF within 30 minutes after birth.

2.2 Preparation Instructions INFASURF does not require reconstitution. Do not dilute or sonicate. INFASURF does not need to reach room temperature before administration. Gently swirl or agitate the INFASURF intratracheal suspension vial for redispersion. Do not shake. Visually inspect the INFASURF intratracheal suspension for discoloration prior to administration. The color of the INFASURF intratracheal suspension should be off-white. Discard the INFASURF vial if the intratracheal suspension is discolored. Visible flecks in the intratracheal suspension and foaming at the surface are normal. Using a 20-gauge or larger needle and syringe to avoid excessive foaming, withdraw INFASURF from the vial. Discard unopened INFASURF vials stored at room temperature for more than 24 hours. Discard unused INFASURF after the initial vial entry.

2.3 Administration Instructions INFASURF should be administered by healthcare providers who are experienced in the acute care of neonates with RDS who require intubation. Two attendants should be present to facilitate dosing; one to instill the INFASURF, the other to monitor the neonate. Administer INFASURF intratracheally through an endotracheal tube using the prepared syringe [ see Dosage and Administration (2.2) ] using either of the following two methods. Instill the INFASURF dose through a: Side-port adapter into the endotracheal tube as two equal aliquots of 1.5 mL/kg each. During and after each aliquot that is instilled, position the neonate with either the right or the left side dependent and maintain ventilation over 20 to 30 breaths for each aliquot, with small bursts timed only during the inspiratory cycles. Between aliquot administration evaluate the respiratory status and reposition to the other side. 5-French feeding catheter inserted into the endotracheal tube as four equal aliquots of 0.75 mL/kg each. During and after each aliquot is instilled, position the neonate in four different positions (i.e., prone, supine, right, and left lateral) to facilitate even distribution of INFASURF. Remove the catheter between each of the instillations and resume mechanical ventilation for 0.5 to 2 minutes. After INFASURF administration, frequently monitor neonate oxygenation and ventilatory status [ see Warnings and Precautions (5.1) ]. For intratracheal administration only (2) The recommended dose of INFASURF is 3 mL/kg body weight at birth. (2.2) Up to 3 doses of INFASURF can be administered. (2.2) Doses should not be given more frequently than every 12 hours. (2.2) Administration instructions: (2.3) Side-port adapter into the endotracheal tube : two equal aliquots while ventilation is continued over 20 to 30 breaths for each aliquot. 5-French feeding catheter inserted into the endotracheal tube : four equal aliquots with the catheter removed between each of the instillations and mechanical ventilation resumed for 0.5 to 2 minutes.

None. None.

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Acute Changes in Oxygenation and Lung Compliance [ see Warnings and Precautions (5.1 )] Administration-Related Adverse Reactions [see Warnings and Precautions (5.2) ]

Intraventricular

Hemorrhage and Periventricular Leukomalacia [ see Warnings and Precautions (5.3) ]

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of INFASURF is based on the pooled safety population from three, randomized, active-controlled clinical trials that evaluated INFASURF to reduce the risk of respiratory distress syndrome (RDS) and rescue treatment of RDS [ see Clinical Studies (14) ], which included 1,554 preterm neonates who received at least one dose of INFASURF. The most common INFASURF administration-related adverse reactions were cyanosis (65%), airway obstruction (39%), bradycardia (34%), reflux of surfactant into the endotracheal tube (21%), requirement for manual ventilation (16%), and reintubation (3%).

6.2 Complications of RDS and Neurodevelopmental Outcomes Incidence of Common Complications of Prematurity The controlled trials of INFASURF included the incidence of common complications of prematurity and RDS as safety endpoints.

Tables

1 and 2 display the results in the INFASURF vs. colfosceril palmitate trials and the INFASURF and beractant trials, respectively.

Trials

1, 2, and 3 were not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the INFASURF and the colfosceril palmitate and beractant treatment groups.

Table

1 Common Complications of Prematurity and RDS in Controlled Trials of INFASURF vs colfosceril palmitate Complication INFASURF (N=1,001) % colfosceril palmitate (N=978) % Apnea 61 61 Patent ductus arteriosus 47 48 Intracranial hemorrhage 29 31 Severe intracranial hemorrhage a 12 10 IVH and PLV b 7 3 Sepsis 20 22 Pulmonary air leaks 12 22 Pulmonary interstitial emphysema 7 17 Pulmonary hemorrhage 7 7 Necrotizing enterocolitis 5 5 a Grade III and IV by the method of Papile. b Patients with both intraventricular hemorrhage and periventricular leukomalacia.

Table

2 Common Complications of Prematurity and RDS Controlled Trials of INFASURF vs beractant Complication INFASURF (N=553) % beractant (N=566) % Apnea 76 76 Patent ductus arteriosus 45 48 Intracranial hemorrhage 36 36 Severe intracranial hemorrhage a 9 7 IVH and PVL b 5 5 Sepsis 28 27 Pulmonary air leaks 15 15 Pulmonary interstitial emphysema 10 10 Pulmonary hemorrhage 7 6 Necrotizing enterocolitis 17 18 a Grade III and IV by the method of Papile. b Patients with both intraventricular hemorrhage and periventricular leukomalacia.

Neurodevelopmental Outcomes

Two-year follow-up data of neurodevelopmental outcomes in 415 neonates who enrolled in the INFASURF vs. colfosceril palmitate controlled-trials demonstrated significant developmental delays in both the INFASURF and colfosceril palmitate groups; however, there was no significant differences between the groups. Most common adverse reactions associated with the use of INFASURF are cyanosis (65%), airway obstruction (39%), bradycardia (34%), reflux of surfactant into the endotracheal tube (21%), requirement for manual ventilation (16%), and reintubation (3%). To report SUSPECTED ADVERSE REACTIONS, contact ONY Biotech Inc. at 1-877-663-4179 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

See

17 for PATIENT COUNSELING INFORMATION

AND PRECAUTIONS

5.1 Acute Changes in Oxygenation and Lung Compliance The administration of exogenous surfactants, including INFASURF, can rapidly affect oxygenation and lung compliance. Frequently monitor neonates who receive INFASURF so that oxygen and ventilatory support can be modified in response to changes in respiratory status. INFASURF should only be administered by those trained and experienced in the care, resuscitation, and stabilization of preterm neonates with RDS who require intubation.

5.2 Administration-Related Adverse Reactions Administration-related adverse reactions associated with INFASURF use included cyanosis, bradycardia, airway obstruction, and reflux of INFASURF into the endotracheal tube. These adverse reactions occurred more frequently in neonates who received repeat doses of INFASURF at 12-hour intervals than neonates that received colfosceril palmitate, the comparator, in randomized controlled trials (Trials 1 and 3) [ see Clinical Studies (14) ]. If these adverse reactions occur during INFASURF administration, stop INFASURF and institute appropriate measures to alleviate these adverse reactions and resume INFASURF with appropriate monitoring.

5.3 Intraventricular Hemorrhage and Periventricular Leukomalacia An increased proportion of INFASURF-treated neonates compared to colfosceril palmitate-treated neonates in randomized clinical trials (Trials 1 and 3) [ see Clinical Studies (14) ] developed intraventricular hemorrhage and periventricular leukomalacia. These adverse reactions were not associated with increased mortality in those studies. In contrast, the same proportion of INFASURF-treated neonates compared to beractant-treated neonates in randomized clinical trials (Trials 2) developed intraventricular hemorrhage and periventricular leukomalacia [ see Adverse Reactions (6.2) ]. While there is no specific treatment for these complications, affected infants may be at increased risk for neurologic complications, including seizures and neurodevelopmental impairment, and should be monitored as per local guidelines.

Acute

Changes in Oxygenation and Lung Compliance: INFASURF administration can rapidly affect oxygenation and lung compliance. Frequently monitor neonates after administration of INFASURF to adjust oxygen therapy and ventilator pressures appropriately. (5.1) Administration-Related Adverse Reactions: Adverse reactions associated with INFASURF include cyanosis, bradycardia, airway obstruction, and reflux of INFASURF into the endotracheal tube. In the event of these adverse reactions, stop INFASURF administration, and take appropriate measures to alleviate the adverse reactions and resume INFASURF with appropriate monitoring. (5.2)

Intraventricular

Hemorrhage and Periventricular Leukomalacia: Some INFASURF-treated neonates developed intraventricular hemorrhage and periventricular leukomalacia in randomized clinical trials. (5.3)