INFASURF

5 WARNINGS 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)

6 ADVERSE 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

<table border="0" width="100%"><caption>Table 1 Common Complications of Prematurity and RDS in Controlled Trials of INFASURF vs colfosceril palmitate</caption><tbody><tr><td><content styleCode="bold">Complication</content></td><td><paragraph><content styleCode="bold">INFASURF</content></paragraph><paragraph><content styleCode="bold">(N=1,001)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td><paragraph><content styleCode="bold">colfosceril palmitate (N=978) </content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td>Apnea</td><td>61</td><td>61</td></tr><tr><td>Patent ductus arteriosus</td><td>47</td><td>48</td></tr><tr><td>Intracranial hemorrhage</td><td>29</td><td>31</td></tr><tr><td>Severe intracranial hemorrhage ^a</td><td>12</td><td>10</td></tr><tr><td>IVH and PLV ^b</td><td>7</td><td>3</td></tr><tr><td>Sepsis</td><td>20</td><td>22</td></tr><tr><td>Pulmonary air leaks</td><td>12</td><td>22</td></tr><tr><td>Pulmonary interstitial emphysema</td><td>7</td><td>17</td></tr><tr><td>Pulmonary hemorrhage</td><td>7</td><td>7</td></tr><tr><td>Necrotizing enterocolitis</td><td>5</td><td>5</td></tr><tr><td><paragraph>^aGrade III and IV by the method of Papile. </paragraph>^bPatients with both intraventricular hemorrhage and periventricular leukomalacia. </td><td/><td/></tr></tbody></table>

<table border="0" width="100%"><caption>Table 2 Common Complications of Prematurity and RDS Controlled Trials of INFASURF vs beractant</caption><tbody><tr><td><content styleCode="bold">Complication</content></td><td><paragraph><content styleCode="bold">INFASURF</content></paragraph><paragraph><content styleCode="bold">(N=553)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td><paragraph>beractant</paragraph><paragraph>(N=566)</paragraph><paragraph>%</paragraph></td></tr><tr><td>Apnea</td><td>76</td><td>76</td></tr><tr><td>Patent ductus arteriosus</td><td>45</td><td>48</td></tr><tr><td>Intracranial hemorrhage</td><td>36</td><td>36</td></tr><tr><td>Severe intracranial hemorrhage ^a</td><td>9</td><td>7</td></tr><tr><td>IVH and PVL ^b</td><td>5</td><td>5</td></tr><tr><td>Sepsis</td><td>28</td><td>27</td></tr><tr><td>Pulmonary air leaks</td><td>15</td><td>15</td></tr><tr><td>Pulmonary interstitial emphysema</td><td>10</td><td>10</td></tr><tr><td>Pulmonary hemorrhage</td><td>7</td><td>6</td></tr><tr><td>Necrotizing enterocolitis</td><td>17</td><td>18</td></tr><tr><td colspan="3"><paragraph>^aGrade III and IV by the method of Papile. </paragraph><paragraph>^bPatients with both intraventricular hemorrhage and periventricular leukomalacia. </paragraph></td></tr></tbody></table>