dia, and decreased cardiac output. if rebound pulmonary hypertension occurs, reinstate genosyl therapy immediately. 5.2 hypoxemia from methemoglobinemia nitric oxide combines with hemoglobin to form methemoglobin, which does not transport oxygen. methemoglobin levels increase with the dose of genosyl; it can take 8 hours or more before steady-state methemoglobin levels are attained. monitor methemoglobin and adjust the dose of genosyl to optimize oxygenation. if methemoglobin levels do not resolve with decrease in dose or discontinuation of genosyl, additional therapy may be warranted to treat methemoglobinemia [see overdosage (10) ] . 5.3 airway injury from nitrogen dioxide nitrogen dioxide (no 2 ) forms in gas mixtures containing no and o 2 . nitrogen dioxide may cause airway inflammation and damage to lung tissues. if there is an unexpected change in no 2 concentration, or if the no 2 concentration reaches 0.5 ppm when measured in the breathing circuit, then the delivery system should be assessed in accordance with the genosyl delivery system operator's manual troubleshooting section, and the no 2 analyzer should be recalibrated. the dose of genosyl and/or fio 2 should be adjusted as appropriate. 5.4 worsening heart failure patients with left ventricular dysfunction treated with genosyl may experience pulmonary edema, increased pulmonary capillary wedge pressure, worsening of left ventricular dysfunction, systemic hypotension, bradycardia and cardiac arrest. discontinue genosyl while providing symptomatic care.

ical support for users of genosyl with the genosyl delivery system . keep available a backup power supply to address power failures. the genosyl delivery system consists of a primary system and a fully functional second system that can be used as backup in the event of primary system failure. monitoring measure methemoglobin within 4-8 hours after initiation of treatment with genosyl and periodically throughout treatment [see warnings and precautions (5.2) ]. monitor for pao 2 and inspired no 2 during genosyl administration [see warnings and precautions (5.3) ]. the concentration of nitric oxide, nitrogen dioxide and air is constantly monitored. the genosyl delivery system will shutdown if nitrogen dioxide reaches 3 ppm. weaning and discontinuation avoid abrupt discontinuation of genosyl [see warnings and precautions (5.1) ]. to wean genosyl, down titrate in several steps, pausing several hours at each step to monitor for hypoxemia.

nts on placebo. total mortality in the pooled trials was 11% on placebo and 9% on nitric oxide gas for inhalation, a result adequate to exclude nitric oxide mortality being more than 40% worse than placebo. in both the ninos and cinrgi studies, the duration of hospitalization was similar in nitric oxide gas for inhalation and placebo-treated groups. from all controlled studies, at least 6 months of follow-up is available for 278 patients who received nitric oxide gas and 212 patients who received placebo. among these patients, there was no evidence of an adverse effect of treatment on the need for re-hospitalization, special medical services, pulmonary disease, and neurological sequelae. in the ninos study, treatment groups were similar with respect to the incidence and severity of intracranial hemorrhage, grade iv hemorrhage, periventricular leukomalacia, cerebral infarction, seizures requiring anticonvulsant therapy, pulmonary hemorrhage, or gastrointestinal hemorrhage. in cinrgi, the only adverse reaction (>2% higher incidence on nitric oxide gas for inhalation than on placebo) was hypotension (14% vs. 11%). 6.2 postmarketing experience post marketing reports of accidental exposure to nitric oxide for inhalation in hospital staff has been associated with chest discomfort, dizziness, dry throat, dyspnea, and headache.

mas), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (cdh), and pulmonary hypoplasia. in these states, pulmonary vascular resistance (pvr) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. in neonates with pphn, nitric oxide gas for inhalation improves oxygenation (as indicated by significant increases in pao 2 ). 12.3 pharmacokinetics the pharmacokinetics of nitric oxide has been studied in adults. absorption and distribution nitric oxide is absorbed systemically after inhalation. most of it traverses the pulmonary capillary bed where it combines with hemoglobin that is 60% to 100% oxygen-saturated. at this level of oxygen saturation, nitric oxide combines predominantly with oxyhemoglobin to produce methemoglobin and nitrate. at low oxygen saturation, nitric oxide can combine with deoxyhemoglobin to transiently form nitrosylhemoglobin, which is converted to nitrogen oxides and methemoglobin upon exposure to oxygen. within the pulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen dioxide and nitrite, respectively, which interact with oxyhemoglobin to produce methemoglobin and nitrate. thus, the end products of nitric oxide that enter the systemic circulation are predominantly methemoglobin and nitrate. metabolism methemoglobin disposition has been investigated as a function of time and nitric oxide exposure concentration in neonates with respiratory failure. the methemoglobin (methb) concentration-time profiles during the first 12 hours of exposure to 0, 5, 20, and 80 ppm nitric oxide are shown in figure 1. methemoglobin concentrations increased during the first 8 hours of nitric oxide exposure. the mean methemoglobin level remained below 1% in the placebo group and in the 5 ppm and 20 ppm nitric oxide gas groups, but reached approximately 5% in the 80 ppm nitric oxide gas group. methemoglobin levels >7% were attained only in patients receiving 80 ppm, where they comprised 35% of the group. the average time to reach peak methemoglobin was 10 ± 9 (sd) hours (median, 8 hours) in these 13 patients, but one patient did not exceed 7% until 40 hours. figure 1 elimination nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for >70% of the nitric oxide dose inhaled. nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration.

function of time and nitric oxide exposure concentration in neonates with respiratory failure. the methemoglobin (methb) concentration-time profiles during the first 12 hours of exposure to 0, 5, 20, and 80 ppm nitric oxide are shown in figure 1. methemoglobin concentrations increased during the first 8 hours of nitric oxide exposure. the mean methemoglobin level remained below 1% in the placebo group and in the 5 ppm and 20 ppm nitric oxide gas groups, but reached approximately 5% in the 80 ppm nitric oxide gas group. methemoglobin levels >7% were attained only in patients receiving 80 ppm, where they comprised 35% of the group. the average time to reach peak methemoglobin was 10 ± 9 (sd) hours (median, 8 hours) in these 13 patients, but one patient did not exceed 7% until 40 hours. figure 1 elimination nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for >70% of the nitric oxide dose inhaled. nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration.

py. hypoxic respiratory failure was caused by meconium aspiration syndrome (mas; 49%), pneumonia/sepsis (21%), idiopathic primary pulmonary hypertension of the newborn (pphn; 17%), or respiratory distress syndrome (rds; 11%). infants 14 days of age (mean, 1.7 days) with a mean pao 2 of 46 mm hg and a mean oxygenation index (oi) of 43 cm h 2 o / mm hg were initially randomized to receive 100% o 2 with (n=114) or without (n=121) 20 ppm nitric oxide for up to 14 days. response to study drug was defined as a change from baseline in pao 2 30 minutes after starting treatment (full response = >20 mm hg, partial = 10-20 mm hg, no response = <10 mm hg). neonates with a less than full response were evaluated for a response to 80 ppm nitric oxide or control gas. the primary results of this study are presented in table 1. table 1: summary of clinical results from hypoxic respiratory failure study control (n=121) nitric oxide gas (n=114) p value death or ecmo death or need for ecmo was the primary end point of this study extracorporeal membrane oxygenation 77 (64%) 52 (46%) 0.006 death 20 (17%) 16 (14%) 0.60 ecmo 66 (55%) 44 (39%) 0.014 although the incidence of death by 120 days of age was similar in both groups (no, 14%; control 17%), significantly fewer infants in the nitric oxide group required ecmo compared with controls (39% vs. 55%, p = 0.014). the combined incidence of death and/or initiation of ecmo showed a significant advantage for the nitric oxide treated group (46% vs. 64%, p = 0.006). the nitric oxide group also had significantly greater increases in pao 2 and greater decreases in the oi and the alveolar-arterial oxygen gradient than the control group (p<0.001 for all parameters). significantly more patients had at least a partial response to the initial administration of study drug in the nitric oxide group (66%) than the control group (26%, p<0.001). of the 125 infants who did not respond to 20 ppm nitric oxide control, similar percentages of no-treated (18%) and control (20%) patients had at least a partial response to 80 ppm nitric oxide gas for inhalation or control drug, suggesting a lack of additional benefit for the higher dose of nitric oxide. no infant had study drug discontinued for toxicity. inhaled nitric oxide gas had no detectable effect on mortality. the adverse events collected in the ninos trial occurred at similar incidence rates in both treatment groups [see adverse reactions (6.1) ] . follow-up exams were performed at 18-24 months for the infants enrolled in this trial. in the infants with available follow-up, the two treatment groups were similar with respect to their mental, motor, audiologic, or neurologic evaluations. cinrgi study this study was a double-blind, randomized, placebo-controlled, multi-center trial of 186 term and near-term neonates with pulmonary hypertension and hypoxic respiratory failure. the primary objective of the study was to determine whether nitric oxide gas would reduce the receipt of ecmo in these patients. hypoxic respiratory failure was caused by mas (35%), idiopathic pphn (30%), pneumonia/sepsis (24%), or rds (8%). patients with a mean pao 2 of 54 mm hg and a mean oi of 44 cm h 2 o / mm hg were randomly assigned to receive either 20 ppm nitric oxide gas (n=97) or nitrogen gas (placebo; n=89) in addition to their ventilatory support. patients who exhibited a pao 2 >60 mm hg and a ph < 7.55 were weaned to 5 ppm nitric oxide gas or placebo. the primary results from the cinrgi study are presented in table 2. table 2: summary of clinical results from persistent pulmonary hypertension of the newborn study placebo nitric oxide gas p value ecmo ecmo was the primary end point of this study extracorporeal membrane oxygenation 51/89 (57%) 30/97 (31%) <0.001 death 5/89 (6%) 3/97 (3%) 0.48 significantly fewer neonates in the nitric oxide gas group required ecmo compared to the control group (31% vs. 57%, p<0.001). while the number of deaths were similar in both groups (nitric oxide gas, 3%; placebo, 6%), the combined incidence of death and/or receipt of ecmo was decreased in the nitric oxide gas group (33% vs. 58%, p<0.001). in addition, the nitric oxide gas group had significantly improved oxygenation as measured by pao 2 , oi, and alveolar-arterial gradient (p<0.001 for all parameters). of the 97 patients treated with nitric oxide gas, 2 (2%) were withdrawn from study drug due to methemoglobin levels >4%. the frequency and number of adverse events reported were similar in the two study groups [see adverse reactions (6.1) ] . in clinical trials, reduction in the need for ecmo has not been demonstrated with the use of inhaled nitric oxide in neonates with congenital diaphragmatic hernia (cdh). 14.2 ineffective in adult respiratory distress syndrome (ards) in a randomized, double-blind, parallel, multicenter study, 385 patients with adult respiratory distress syndrome (ards) associated with pneumonia (46%), surgery (33%), multiple trauma (26%), aspiration (23%), pulmonary contusion (18%), and other causes, with pao 2 /fio 2 <250 mm hg despite optimal oxygenation and ventilation, received placebo (n=193) or nitric oxide gas (n=192), 5 ppm, for 4 hours to 28 days or until weaned because of improvements in oxygenation. despite acute improvements in oxygenation, there was no effect of nitric oxide gas on the primary endpoint of days alive and off ventilator support. these results were consistent with outcome data from a smaller dose ranging study of nitric oxide (1.25 to 80 ppm). genosyl (nitric oxide) for inhalation is not indicated for use in ards. 14.3 ineffective in prevention of bronchopulmonary dysplasia (bpd) the safety and efficacy of nitric oxide gas for the prevention of chronic lung disease [bronchopulmonary dysplasia (bpd)] in neonates ≤ 34 weeks gestational age requiring respiratory support has been studied in four large previously conducted multicenter, double-blind, placebo-controlled clinical trials in a total of 2,600 preterm infants. of these, 1,290 received placebo, and 1,310 received inhaled nitric oxide at doses ranging from 5-20 ppm, for treatment periods of 7-24 days duration. the primary endpoint for these studies was alive and without bpd at 36 weeks postmenstrual age (pma). the need for supplemental oxygen at 36 weeks pma served as a surrogate endpoint for the presence of bpd. overall, efficacy for the prevention of bronchopulmonary dysplasia in preterm infants was not established. there were no meaningful differences between treatment groups with regard to overall deaths, methemoglobin levels, or adverse events commonly observed in premature infants, including intraventricular hemorrhage, patent ductus arteriosus, pulmonary hemorrhage, and retinopathy of prematurity. the use of genosyl (nitric oxide) for prevention of bpd in preterm neonates ≤34 weeks gestational age is not recommended.