Earlier Use of Inhaled Nitric Oxide in Term and Near-Term Neonates With Hypoxic Respiratory Failure (HRF) and Pulmonary Hypertension (PH)

Earlier Use of Inhaled Nitric Oxide in Term and Near-Term Neonates With Hypoxic Respiratory Failure (HRF) and Pulmonary Hypertension (PH) 2013 Ikaria, Inc. 1

Disclosure Information This program is sponsored by Ikaria, manufacturer of INOMAX (nitric oxide) for inhalation. 2

Outline Acute Hypoxic Respiratory Failure (HRF) in Newborns: The Clinical Problem Physiologic Approach to HRF Earlier Use of Inhaled Nitric Oxide (ino) in the Treatment of HRF 3

HRF in the Newborn: A Definition A relative deficiency of oxygen in arterial blood, often associated with insufficient ventilation. 1 This deficiency can be reflected by progressive respiratory and metabolic acidosis and remains a persistent challenge in the management of some newborns. 1. Williams LJ, et al. Neonatal Netw. 2004;23:5-13.. 4

Question 1 In an average month how many term/near-term infants (>34 weeks gestation) with hypoxic respiratory failure (HRF)/persistent pulmonary hypertension of the neonate (PPHN) does your unit treat? A. 0 5 B. 6 10 C. 10 5

Ventilation Rate (per 1000 live births) Epidemiology of Neonatal HRF 900 9 800 8 Ventilation Rate 700 7 600 6 Percent of all births 500 400 300 5 4 3 Percent Percent of mechanical ventilation admissions 200 2 100 1 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 0 Birth Weight (grams) Adapted with permission from Angus DC, et al. Am J Respir Crit Care Med. 2001;164:1154-1160. 6

HRF in Newborns: Some Commonly Occurring Diseases Idiopathic PPHN Respiratory Distress Syndrome Meconium Aspiration Syndrome Congenital Diaphragmatic Hernia No underlying lung disease Acute lung injury Surfactant deficiency or inactivation Pulmonary edema, volume loss Airway obstruction with gas trapping Surfactant inactivation Pneumonitis Lung hypoplasia Decreased vascular surface area Increased pulmonary artery muscularity Images courtesy of John P. Kinsella, MD, and Steven H. Abman, MD. 7

Pathophysiology of HRF: The Cardiopulmonary Triad 1,2 Lung disease Low and high lung volumes Regional gas trapping, hyperinflation Cardiac disease Left ventricular dysfunction High right ventricular pressure Pulmonary vascular disease Increased vascular tone and reactivity Decreased vascular growth (lung hypoplasia) Hypertensive vascular remodeling 1. Kinsella JP. Early Hum Dev. 2008:84:709-716. 2. Kinsella JP, Abman SH. J Pediatr. 1995;126:853-864. 8

Cardiopulmonary Interactions in Neonatal HRF PVR SVR Right-to-left shunting at PDA or FO Hypoxia, hypercapnia, acidosis High vascular tone Altered reactivity Structural disease Hypovolemia RV pressure overload LV dysfunction Lung volume Compliance Intrapulmonary shunt Adapted with permission from Kinsella JP, Abman SH. J Pediatr. 1995;126:853-864. 9

HRF in Newborns: Pathophysiology 1 Intrapulmonary shunt: pulmonary arterial blood reaches the pulmonary venous side without passing through ventilated areas of the lung Extrapulmonary shunt (PPHN): right-to-left shunting of blood bypasses the lung through fetal channels (ductus arteriosus and/or foramen ovale) Ventilation perfusion (V/Q) mismatch: imbalance between ventilation and perfusion; alveolar hypoxia, increased dead-space ventilation 1. Kinsella JP. Early Hum Dev. 2008;84:709-716. 10

Intrapulmonary Shunting PV PA PA = pulmonary artery; PV = pulmonary vein. 11

HRF in Newborns: Pathophysiology 1 Extrapulmonary shunt (PPHN): right-to-left shunting of blood bypasses the lung through fetal channels (ductus arteriosus and/or foramen ovale) 1. Kinsella JP. Early Hum Dev. 2008;84:709-716. 12

Extrapulmonary Shunting Normal Blood Flow to To the Lungs Lungs Right Atrium Foramen Ovale Blood Flow to Body Normal Normal Blood Flow Blood Flow to the To Lungs From Blood the Flow Lungs Lungs From the Lungs Left Atrium Reduced Oxygenation RBC [Deoxygenated] RBC [Oxygenated] Some Blood Bypasses the Lungs Left Ventricle RBC [Low Oxygenation] Right Ventricle RBC, red blood cell. Adapted from Aschner JL, Fike CD. New Developments in the Pathogenesis and Management of Neonatal Pulmonary Hypertension. In: Bancalari E, Polin RA, eds. The Newborn Lung Neonatology Questions and Controversies. Philadelphia; Saunders: 2008:242, Figure 12-1. Property of Ikaria, Inc. 13

HRF in Newborns: Pathophysiology 1 Ventilation perfusion (V/Q) mismatch: imbalance between ventilation and perfusion; alveolar hypoxia, increased dead-space ventilation 1. Kinsella JP. Early Hum Dev. 2008;84:709-716. 14

Optimal Oxygenation Requires Matching Ventilation and Perfusion (V/Q) 1 MISMATCHED Low inflation to perfusion MISMATCHED High inflation with low perfusion MATCHED Inflation/perfusion (V/Q ~ 1) Poor ventilation despite perfusion produces hypoxemia Intrapulmonary shunting Inflation recruits the lung, but with low blood flow Hypoxemia persists Adequate ventilation with perfusion optimizes oxygenation V/Q matching occurs 1. Kinsella JP. Early Hum Dev. 2008;84:709-716. 15

Adequately Recruiting the Lung: Optimizing Lung Volume Is the First Step Overdistention and underinflation contribute to high PVR High lung volume ventilation overdistends, resulting in volutrauma Low lung volume ventilation tears adhesive surfaces Figure reprinted from Froese AB. Crit Care Med. 1997;25:906-908. Copyright 2009, with permission from Society of Critical Care Medicine. 16

PVR PVR Can Increase at Low or High Lung Volumes Lung Volume Images courtesy of John P Kinsella, MD, and Steven H. Abman, MD. 17

Treatment of Neonatal HRF 1,2 Lung Optimize lung volume and ventilation Heart Enhance cardiac function and systemic blood pressure Pulmonary vascular disease Lower PVR Improve ventilation perfusion mismatch by redirecting blood from poorly aerated or diseased lung regions to better aerated distal air spaces 1. Froese AB. Crit Care Med. 1997;25:906-908. 2. Kinsella JP. Early Hum Dev. 2008;84:709-716. 18

Important Safety Information When Using INOMAX 1 Indication INOMAX is a vasodilator, which, in conjunction with ventilatory support and other appropriate agents, is indicated for the treatment of term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation Utilize additional therapies to maximize oxygen delivery with validated ventilation systems 1. INOMAX [package insert]. Hampton, NJ: Ikaria, Inc.; 2013. 19

Important Safety Information When Using INOMAX-- Contraindication 1 Inhaled nitric oxide must not be used in the treatment of neonates known to be dependent on right-to-left shunting of blood. 1. INOMAX [package insert]. Hampton, NJ: Ikaria, Inc.; 2013. 20

In the CINRGI Study, Clinical Evidence of PPHN Was Defined as One of the Following: A B Differential Oxygenation >2 Desaturation Events in 12 hours Preductal Differential oxygenation in preductal and postductal areas (ie, 5% difference in preductal and postductal saturations by pulse oximetry or arterial blood gases) 3 Postductal Marked clinical lability in oxygenation despite optimized treatment of the neonate s lung disease Marked clinical lability is defined as more than 2 desaturation (SaO 2 <85%) events occurring within a 12-hour period a 1 2 a The attending physician must attribute the desaturation events to PPHN and not to changes in lung disease or ventilator strategy. SaO 2, arterial oxygen saturation. Clark RH, et al. N Engl J Med. 2000;342:469-474. 21

Inhaled Nitric Oxide Causes Selective Pulmonary Vasodilation Reprinted from Wessel DL, Adatia I. In: Ignarro L, Murad F, eds. Advances in Pharmacology: Nitric Oxide: Biochemistry, Molecular Biology, and Therapeutic Implications. Vol. 34. New York, NY: Academic Press; 1995:425-498. Copyright 1995, with permission from Elsevier. 22

Underinflation Creates V/Q Mismatching 1 Underventilated portion of lung Decreased PaO 2 Increased pulmonary artery pressure and decreased blood flow PV PA PA = pulmonary artery; PV = pulmonary vein. 1. Rossaint R, et al. N Engl J Med. 1993;328:399-405. 23

Inhaled Nitric Oxide (ino) Reduces V/Q Mismatching 1 Inhaled NO increases vasodilation Decreases pulmonary artery pressure Increases PaO 2 and blood flow in better ventilated regions Improves V/Q ratios in neonates with HRF PV NO NO PA PA = pulmonary artery; PV = pulmonary vein; NO = nitric oxide. 1. Rossaint R, et al. N Engl J Med. 1993;328:399-405. 24

An Inhaled Vasodilator Inhalation of NO offers selective activity The only FDA-approved drug that selectively dilates the pulmonary vasculature 1 Targeted delivery to the pulmonary bed 1 Inhalation of NO offers rapid onset Clinical responses seen in as little as 30 minutes 1 Inhaled nitric oxide causes vasodilation in the pulmonary vasculature 1 Inhalation of NO offers rapid clearance Rapid inactivation by hemoglobin minimizes systemic effects 1,2 Nitrate, the predominant metabolite of nitric oxide, is rapidly cleared by the kidneys 1 1. INOMAX [package insert]. Hampton, NJ: Ikaria, Inc.; 2013. 2. Steudel W, et al. Anesthesiology. 1999;91:1090-1121. 25

Inhaled Nitric Oxide Phase III Studies for Neonatal HRF Objective CINRGI 1,2 NINOS 2,3 I-NO/PPHN 2,4 to reduce the need for ECMO to reduce mortality and/or the need for ECMO to reduce the incidence of death, ECMO, neurologic injury, or BPD Design 186 term/near-term infants (>34 weeks) with HRF and PPHN 235 term/near-term infants (>34 weeks) with HRF and PPHN 155 term infants* ( 37 weeks) with HRF and PPHN *Trial halted due to slow enrollment ino Dose 20 ppm, weaned to 5 ppm 20 ppm, with possible increase to 80 ppm 5, 20, or 80 ppm 1. Clark RH, et al. N Engl J Med. 2000;342:469-474. 2. INOMAX [package insert]. Hampton, NJ: Ikaria, Inc.; 2013. 3. The Neonatal Inhaled Nitric Oxide Study Group. N Engl J Med. 1997;336:597-604. 4. Davidson D, et al. Pediatrics. 1998;101:325-334. 26

Events ( %) 30-Minute Change From Baseline (mm Hg) CINRGI: Efficacy Outcomes 1,2 Primary Outcome Secondary Outcome 70 N=186 P<0.001 0 N=168 60 58 57-10 50-20 40 30 33 31-30 -40-23 P<0.001 20 10 0 6 3 Death and/or ECMO Death ECMO * -50-60 -59.5 PA-aO 2 (A:a gradient) Placebo Inhaled NO *Primary outcome. 1. INOMAX [package insert]. Hampton, NJ: Ikaria, Inc.; 2013. 2. Data on file. Hampton, NJ: Ikaria; 2009. 27

Proportion of Patients Requiring Oxygen Therapy CINRGI: Retrospective Analysis 1 Inhaled nitric oxide shortens median time on oxygen therapy (17 vs 34 days) 1.00 Ventilation (n=102) Ventilation + ino (n=110) 0.75 P=0.0264 for log-rank test 0.50 0.25 0.00 17 Days 34 Days 0 20 40 60 80 100 120 Days Time on oxygen therapy shown in a Kaplan-Meier analysis of retrospective data from the CINRGI phase III study. Median oxygen time is defined as the day at which 50% of patients went off oxygen therapy. Patients who died or received extracorporeal membrane oxygenation are censored. Total length of hospital stay was not different between study groups. CINRGI was not sufficiently powered to show significance in this endpoint. 1. Data on file. Hampton, NJ: Ikaria, Inc.; 1999. 28

Events ( %) 30-Minute Change From Baseline (mm Hg) NINOS: Efficacy Outcomes 1,2 Primary Outcome Secondary Outcome 70 60 50 40 P=0.006 64 46 N=235 P=0.014 55 39 0-10 -20-30 -6.7 P<0.001 30 P=0.60-40 -50 20 10 17 14-60 -70-60 0 * Death and/or ECMO Death ECMO PA-aO 2 (A-a gradient) Placebo ino *Primary outcome. 1. INOMAX [package insert]. Hampton, NJ: Ikaria, Inc.; 2013. 2. The Neonatal Inhaled Nitric Oxide Study Group. N Engl J Med. 1997;336:597-604. 29

Safety Outcomes From Phase III Studies Results from NINOS and CINRGI studies 1 Combined mortality: placebo (11%); inhaled NO (9%) In CINRGI, the only adverse reaction (>2% higher incidence on INOmax than placebo) was hypotension (14% vs. 11%) Treatment groups were similar with respect to incidence and severity of intracranial hemorrhage, periventricular leukomalacia, cerebral infarction, seizures requiring anticonvulsant therapy, and pulmonary or gastrointestinal hemorrhage 6-month follow-up: inhaled NO (n=278); control (n=212) No differences in pulmonary disease or neurological sequelae, or in the need for rehospitalization or special medical services 1. INOMAX [package insert]. Hampton, NJ: Ikaria, Inc.; 2013. 30

Question 2 What is the most important parameter you use to classify the severity of HRF/PPHN of the term/near-term newborn? A. Oxygenation Index (OI) B. Partial pressure of arterial O 2 (PaO 2 ) C. Level of PEEP D. Level of mean airway pressure (P aw ) E. A-a Gradient or A-aDO 2 F. None of the above 31

Question 3 What is your typical Oxygenation Index (OI) threshold for the initiation of inhaled NO in a term/near-term infant with HRF associated with pulmonary hypertension? A. <15 B. 15-19 C. 20 24 D. >25 E. Do not use OI for initiation 32

When Is the Right Time to Initiate Inhaled Nitric Oxide? Use of Oxygenation Index (OI) in term and near-term neonatal HRF Compares the level of ventilator support (FiO 2 and mean airway pressure [MAP]) with the resultant systemic arterial oxygen levels OI = FiO 2 mean airway pressure 100 postductal PaO 2 [Example: FiO 2, 0.60; MAP, 15; PaO 2, 50 torr = (0.60 15 100)/50 = 18 OI] Mild Moderate Severe Very Severe Trachsel D, et al. Am J Respir Crit Care Med. 2005;172:206-211. 33

Additional Publications to Address Earlier Use of ino in Infants With HRF Konduri GG, Solimano A, Sokol GM, et al. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics. 2004;113(3 pt 1):559-564. Golombek SG, Young JN. Efficacy of inhaled nitric oxide for hypoxic respiratory failure in term and late preterm infants by baseline severity of illness: a pooled analysis of three clinical trials. Clin Ther. 2010;32(5):939-948. González A, Fabres J, D'Apremont I, et al. Randomized controlled trial of early compared with delayed use of inhaled nitric oxide in newborns with a moderate respiratory failure and pulmonary hypertension. J Perinatol. 2010;30(6):420-424. 34

Konduri et al 2004: Study Design 1 Prospective, randomized, controlled, double-masked, multicenter trial Patients: 299 infants ( 34 weeks gestation) with respiratory failure that needed assisted ventilation OI 15 and <25 (mild to moderate severity) on FiO 2 0.80 Dosing: ino initiated at 5 ppm or simulated (sham) dose Dose increased to 20 ppm if the increase in PaO 2 was 20 mm Hg Infants in either group were transitioned to standard ino if OI increased to 25 Objective: To determine whether early ino administration results in additional reduction of the incidence of ECMO or death 1. Konduri GG, et al. Pediatrics. 2004;113(3 pt 1):559-564. 35

Percent of Patients Konduri et al 2004: Primary Outcome 1 25 20 15 10 5 0 19.5% (29/149) n=149 P=0.53 Primary outcome: death by day 120 or ECMO Control 16.7% (25/150) n=150 Early ino The primary outcome incidence observed in the control group (19.5%) is approximately half of the projected incidence on the basis of our 1997 pilot data. The mean OI at enrollment in study infants was nearly 20, and a lack of a clear separation between early and standard ino groups may have contributed to the lack of treatment effect in our study. ino improves oxygenation but does not reduce the incidence of ECMO/mortality when initiated at an OI of 15 to 25 compared with initiation at >25 in term and near-term neonates with respiratory failure. 1. Konduri GG, et al. Pediatrics. 2004;113(3 pt 1):559-564. 36

Konduri et al 2004: Additional Outcomes 1 More infants in the early ino group had >20 mm Hg increase in PaO 2 in response to study gas initiation compared with the control group (P<0.001) 73% of early ino infants 37% of control infants SELECT SECONDARY OUTCOMES Variable Early ino group (n=150) Control group (n=149) P value Duration of study gas administration* 57 ± 48 hours 39 ± 38 hours <0.003 Initiation of standard ino therapy (OI > 25) 61 (41%) 81 (54%) <0.02 Progression of OI >40 11 (7%) 21 (14%) 0.056 *Mean ± standard deviation. 1. Konduri GG, et al. Pediatrics. 2004;113(3 pt 1):559-564. 37

Konduri et al 2004: Safety 1 None of the study infants had study gas weaned or discontinued because of elevated methemoglobin or NO 2 levels 1 ino infant and 2 control infants developed severe (grade 3-4) intraventricular hemorrhage and periventricular leukomalacia Seizures occurred in 14 ino infants (9.4%) and 11 control infants (7.4%) (P=0.68) 1. Konduri GG, et al. Pediatrics. 2004;113(3 pt 1):559-564. 38

Percent Risk for ECMO or Death Konduri et al 2013: Risk of ECMO/death by OI at enrollment 1* 30% 25% 20% 15% 10% p = 0.02 n = 88 n = 62 60% relative reduction in ECMO/death 5% 0% Early ino: OI = 15 to <20 Early ino: OI =20 to < 25 *Post-hoc, subgroup analysis of prospectively collected data from the early ino RCT to identify factors associated with ECMO/death and progression of HRF. 39 1. Konduri GG, et al. Journal of Perinatology. 2013.

Percent Risk for ECMO or Death Konduri et al 2013: Risk of ECMO/death by treatment assignment and OI at enrollment 1* 20% 15% p = 0.16 n = 92 10% n = 88 41% relative reduction in ECMO/death 5% 0% Early ino: OI = 15 to <20 Control Ϯ : OI = 15 to <20 *Post-hoc, subgroup analysis of prospectively collected data from the early ino RCT to identify factors associated with ECMO/death and progression of HRF. Ϯ The control group was eligible to receive ino if their HRF progressed to an OI > 25 40 1. Konduri GG, et al. Journal of Perinatology. 2013.

Percent Risk for Progression to OI >30 Konduri et al 2013: Progression of HRF * 35% n = 149 30% 25% 20% 15% 10% 5% p = 0.002 n = 150 0% 1. Konduri GG, et al. Journal of Perinatology. 2013. Early ino: OI >30 Control Ϯ : OI >30 *Post-hoc, subgroup analysis of prospectively collected data from the early ino RCT to identify factors associated with ECMO/death and progression of HRF. Ϯ The control group was eligible to receive ino if their HRF progressed to an OI > 25 41

Question 4 What would you consider to be a maximal (amount) of FiO 2 to obtain adequate oxygenation (PaO 2 60 mmhg) for a term/near-term infant with HRF/PPHN? A. <.30 B. <.60 C. <.80 D. <.90 E. 1.0 42

Question 5 Assuming a less than optimal response in oxygenation, how long would you maintain a patient on a FiO 2 of 1.0 prior to ino initiation with a term/near-term infant with HRF/PPHN? A. 0 B. >0 but <1 hour C. 1 hour D. >1 hour 43

Golombek et al: Study Design 1 Objectives To analyze the effects of inhaled nitric oxide on measures of oxygenation To analyze the effects of inhaled nitric oxide across a range of illness severity strata To analyze the effects of inhaled nitric oxide on the duration of mechanical ventilation Methods A retrospective pooled analysis of all subjects receiving 20 ppm inhaled nitric oxide in the CINRGI, NINOS, and I-NO/PPHN Phase III trials No censoring based on underlying diagnosis or baseline characteristics 1. Golombek SG, et al. Clin Ther. 2010;32:939-948 44

Change in mean PaO 2 at 30 Minutes (mm Hg [kpa]) Golombek et al: Oxygenation Results 1 Inhaled nitric oxide causes rapid improvement (at 30 min) in oxygenation P<0.001 P=0.046 P<0.001 P<0.001 80 60 60.28 54.64 54.91 Ventilation 40 20 8.85 38.63 17.95 19.08 14.15 Ventilation + ino Baseline 0 NINOS I-NO/PPHN CINRGI All Studies (N=227) (N=75) (N=186) (N=493) 1. Golombek SG, et al. Clin Ther. 2010;32:939-948. 45

Change in mean PaO 2 at 30 Minutes by Baseline OI (mm Hg [kpa]) Golombek et al: Oxygenation Results 1 Inhaled NO improves oxygenation in severe and very severe HRF Severe Very Severe 80 P<0.001 P<0.001 60 62.07 45.17 Ventilation 40 Ventilation + ino 20 13.95 18.66 0 Baseline OI = >25 to 40 >40 (n=170) (n=186) 1. Golombek SG, et al. Clin Ther. 2010;32:939-948. 46

Change in mean PaO 2 at 30 Minutes by Baseline OI (mm Hg [kpa]) Golombek et al: Oxygenation Results 1 Inhaled NO improves oxygenation even in mild and moderate HRF Mild Moderate Severe Very Severe 80 60 40 P=0.003 62.39 P=0.004 52.93 P<0.001 62.07 P<0.001 45.17 Ventilation 20 0 18.28 13.95 18.66 Ventilation + ino -20-40 Baseline OI = -23.03 15 >15 to 25 >25 to 40 >40 (n=40) (n=91) (n=170) (n=186) 1. Golombek SG, et al. Clin Ther. 2010;32:939-948. 47

Proportion of Patients Requiring Mechanical Ventilation Golombek et al: Time on Vent Results 1 Inhaled NO reduces median days on mechanical ventilation (11 vs. 14 days) 1.00 0.75 Placebo ino 20 ppm 0.50 P=0.003 0.25 0.00 0 10 20 30 40 50 Days on Mechanical Ventilation This is a Kaplan-Meier analysis of pooled data from 3 independent controlled studies, NINOS, CINRGI, and I-NO/PPHN (N=243). Outliers are removed for visual purposes. 1. Golombek SG, et al. Clin Ther. 2010;32:939-948. 48

González et al: Study Design 1 Prospective, randomized, controlled, open-label, two-center trial Patients: 56 term/near-term infants ( 35 weeks gestation) with HRF and PPHN OI between 10 and 30 (mild to moderate severity) Dosing: 20 ppm, weaned to 5 ppm Objective: to evaluate whether early treatment with ino can prevent infants with moderate respiratory failure from developing severe HRF (OI 40) 1. González A, et al. J Perinatol. 2010;30:420-424. 49

Percent of Patients Experiencing Treatment Failure González et al: Treatment Failure Outcomes 1 Early ino significantly decreased the probability of developing severe disease as shown by the primary endpoint, treatment failure 70 60 50 40 30 20 10 0 61% (17/28) n=28 25% (7/28) n=28 P<0.05 Placebo ino Treatment Failure (OI >40 within 48 hours) 1. González A, et al. J Perinatol. 2010;30:420-424. 50

Oxygenation Index González et al: OI Outcomes Early ino significantly reduced OI over time in infants with mild to moderate HRF 40 35 Early ino Control * 17 of the 28 control infants reached an OI >40 and were switched to ino 30 * * 25 * *P<0.01 20 15 10 0 4 12 24 48 Time (hours) Adapted with permission from González A, et al. J Perinatol. 2010;30:420-424. 51

González et al: Days on Oxygen Therapy Early ino significantly reduced the median time on oxygen therapy (11.5 days vs 18 days, P<0.03) Survival plot of the probability of oxygen therapy requirement after enrollment in the trial. Adapted with permission from González A, et al. J Perinatol. 2010;30:420-424. 52

González et al: Safety 1 Patients treated with ino did not have elevated blood levels of methemoglobin or high levels of NO 2 in the ventilatory circuit There were no differences between groups in the incidence of other neonatal complications such as bleeding and/or coagulation disorders, hypotension, or infections 1. González A, et al. J Perinatol. 2010;30:420-424. 53

Inhaled Nitric Oxide Delivery Systems INOmax DS IR Compatible with most neonatal ventilators and modes of ventilation* *Please see sales representative to find out if your ventilator is compatible. 54

Guidelines for Weaning Patients Off ino ino should be maintained up to 14 days or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from ino therapy Abrupt discontinuation of ino may lead to increasing pulmonary artery pressure and worsening oxygenation even in neonates with no apparent response to NO for inhalation To wean ino, down titrate in several steps, pausing several hours at each step to monitor for hypoxemia If rebound pulmonary hypertension occurs, reinstate ino therapy immediately INOMAX [package insert]. Hampton, NJ: Ikaria, Inc.; 2013. 55

Important Safety Information When Using Inhaled Nitric Oxide-- Contraindication 1 Inhaled nitric oxide must not be used in the treatment of neonates known to be dependent on right-to-left shunting of blood. 1. INOMAX [package insert]. Hampton, NJ: Ikaria, Inc.; 2013. 56

Important Safety Information When Using Inhaled Nitric Oxide 1 Rebound Abrupt discontinuation of INOmax may lead to increasing pulmonary artery pressure and worsening oxygenation even in neonates with no apparent response to nitric oxide for inhalation. Methemoglobinemia and NO 2 levels Increases with dose of ino Nitric oxide donor compounds may have an additive effect with INOmax on the risk of developing methemoglobinemia Nitrogen dioxide may cause airway inflammation and damage to lung tissues Monitor for PaO 2, methemoglobin, and inspired NO 2 during INOmax administration. Pre-existing left ventricular dysfunction Inhaled NO may increase pulmonary capillary wedge pressure leading to pulmonary edema Use only with an INOmax DS IR, INOmax DS, or INOvent operated by trained personnel 1. INOMAX [package insert]. Hampton, NJ: Ikaria, Inc.; 2013. 57

Methemoglobin Levels, % Methemoglobin Levels 1 6 5 4 3 2 1 0 2 4 6 8 10 12 Hours Inhaled nitric oxide (ppm): 80 20 5.0 Control 1. INOMAX [package insert]. Hampton, NJ: Ikaria, Inc.; 2013. 58

Key Takeaways HRF continues to be a therapeutic challenge Inhaled nitric oxide, combined with adequate ventilation, can improve oxygenation in neonates with HRF at all levels of disease severity Earlier use of inhaled nitric oxide in neonates with respiratory failure may improve oxygenation 1 and decrease the probability of developing severe HRF 2 Inhaled nitric oxide is well tolerated. Adverse reactions, rebound pulmonary hypertension, methemoglobinemia, and increased NO 2 are manageable and dose related 3 1. Golombek SG, et al. Clin Ther. 2010;32:939-948. 2. González A, et al. J Perinatol. 2010;30:420-424. 3. INOMAX [package insert]. Hampton, NJ: Ikaria, Inc.; 2013. 59