INOmaxTM (nitric oxide gas) is a drug administered by inhalation. Nitric oxide, the active substance in INOmax, is a pulmonary vasodilator. INOmax is a gaseous blend of nitric oxide (0.8%) and nitrogen (99.2%). INOmax is supplied in aluminum cylinders as a compressed gas under high pressure (2000 pounds per square inch gauge [psig]).

INOmax appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios.

Effects on Pulmonary Vascular Tone in PPHN: Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (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, INOmax improves oxygenation (as indicated by significant increases in PaO2).

The efficacy of INOmax has been investigated in term and near-term newborns with hypoxic respiratory failure resulting from a variety of etiologies. Inhalation of INOmax reduces the oxygenation index (OI= mean airway pressure in cm H2O x fraction of inspired oxygen concentration [FiO2] x 100 divided by systemic arterial concentration in mm Hg [PaO2]) and increases PaO2 (See CLINICAL PHARMACOLOGY.)

(i) NINOS study: The Neonatal Inhaled Nitric Oxide Study (NINOS) group conducted a double-blind, randomized, placebo-controlled, multicenter trial in 235 neonates with hypoxic respiratory failure. The objective of the study was to determine whether inhaled nitric oxide would reduce the occurrence of death and/or initiation of extracorporeal membrane oxygenation (ECMO) in a prospectively defined cohort of term or near-term neonates with hypoxic respiratory failure unresponsive to conventional therapy. Hypoxic respiratory failure was caused by meconium aspiration syndrome (MAS; 49%), pneumonia/sepsis (21%), idiopathic primary pulmonary hypertension if the newborn (PPHN; 17%), or respiratory distress syndrome (RDS; 11%). Infants £ 14 days of age (mean, 1.7 days) with a mean PaO₂ of 46 mm Hg and a mean oxygenation index (OI) of 43 cm H₂O / mm Hg were initially randomized to receive 100% O₂ 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 PaO2 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 from the NINOS study are presented in Table 1.

a Extra-corporeal membrane oxygenation

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 PaO2 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 or control, similar percentages of NO-treated (18%) and control (20%) patients had at least a partial response to 80 ppm nitric oxide 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. Inhalednitric oxide 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.) Follow-up exams were performedat 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 theirmental, motor, audiologic, or neurologic evaluations.

(ii) CINRGI study: This study was a double-blind, randomized, placebo-controlled, multicenter 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 INOmax 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 PaO₂ of 54 mm Hg and a mean (OI) of 44 cm H₂O / mm Hg were randomly assigned to receive either 20 ppm INOmax (n=97) or nitrogen gas (placebo; n=89) in addition to their ventilatory support. Patients who exhibited a PaO2 >60 mm Hg and a pH < 7.55 were weaned to 5 ppm INOmax or placebo. The primary results from the CINRGI study are presented in Table 2.

a Extra-corporeal membrane oxygenation

In addition, the INOmax group had significantly improved oxygenation as measured by PaO2, OI, and alveolar-arterial gradient (p<0.001 for all parameters). Of the 97 patients treated with INOmax, 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.)

In one study, NO2 levels were <0.5 ppm when neonates were treated with placebo, 5 ppm, and 20 ppm nitric oxide over the first 48 hours. The 80 ppm group had a mean peak NO2 level of 2.6 ppm.

No formal drug-interaction studies have been performed, and a clinically significant interaction with other medications used in the treatment of hypoxic respiratory failure cannot be excluded based on the available data. In particular, although there are no data to evaluate the possibility, nitric oxide donor compounds, including sodium nitroprusside and nitroglycerin, may have an additive effect with INOmax on the risk of developing methemoglobinemia. INOmax has been administered with tolazoline, dopamine, dobutamine, steroids, surfactant, and high-frequency ventilation.

INOmax should be administered with monitoring for PaO₂, methemoglobin, and NO2.

The nitric oxide delivery systems used in the clinical trials provided operator-determined concentrations of nitric oxide in the breathing gas, and the concentration was constant throughout the respiratory cycle. INOmax must be delivered through a system with these characteristics and which does not cause generation of excessive inhaled nitrogen dioxide. The INOvent™ system and other systems meeting these criteria were used in the clinical trials. In the ventilated neonate, precise monitoring of inspired nitric oxide and NO2 should be instituted, using a properly calibrated analysis device with alarms. This system should be calibrated using a precisely defined calibration mixture of nitric oxide and nitrogen dioxide, such as INOcalä . Sample gas for analysis should be drawn before the Y-piece, proximal to the patient. Oxygen levels should also be measured.

The INOmax dose should not be discontinued abruptly as it may result in an increase in pulmonary artery pressure and/or worsening of blood oxygenation (PaO2). Deterioration in oxygenation and elevation in PAP may also occur in children with no apparent response to INOmax. Discontinue/wean cautiously.

The exposure limit set by the Occupational Safety and Health Administration (OSHA) for nitric oxide is 25 ppm and for NO2 the limit is 5 ppm.