Nitric Oxide

INOmax ® is indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents. INOmax is a vasodilator indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents.

The recommended dose is 20 ppm, maintained for up to 14 days or until the underlying oxygen desaturation has resolved ( 2.1 ). Doses greater than 20 ppm are not recommended ( 2.1 , 5.2 ) Administration: Avoid abrupt discontinuation ( 2.2 , 5.1 ).

2.1 Dosage Term and near-term neonates with hypoxic respiratory failure The recommended dose of INOmax is 20 ppm. Maintain treatment up to 14 days or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from INOmax therapy. Doses greater than 20 ppm are not recommended [see Warnings and Precautions (5.2) ] .

2.2 Administration Nitric Oxide Delivery Systems INOmax must be administered using a calibrated, FDA-cleared Nitric Oxide Delivery System (NODS). There are various FDA-cleared NODS; refer to the NODS labeling to determine which NODS to use with this drug product and for needed information on training and technical support for users of this drug product with the NODS. When utilizing a nitric oxide delivery system specifically cleared for use in the MRI suite (e.g., the INOmax DSIR ® Plus MRI) only use INOmax MR conditional cylinders at 100 gauss or less [see How Supplied/Storage and Handling (16) ]. Keep available a backup battery power supply and an independent reserve nitric oxide delivery system to address power and system failures . Monitoring Measure methemoglobin within 4-8 hours after initiation of treatment with INOmax and periodically throughout treatment [see Warnings and Precautions (5.2) ] . Monitor for PaO 2 and inspired NO 2 during INOmax administration [see Warnings and Precautions (5.3) ] . Weaning and Discontinuation Avoid abrupt discontinuation of INOmax [see Warnings and Precautions (5.1) ]. To wean INOmax, downtitrate in several steps, pausing several hours at each step to monitor for hypoxemia.

INOmax (nitric oxide) gas is available in 800 and 4,880 ppm concentrations. INOmax (nitric oxide) is a gas available in 800 and 4,880 ppm concentrations ( 3 ).

INOmax is contraindicated in neonates dependent on right-to-left shunting of blood. Neonates dependent on right-to-left shunting of blood ( 4 ).

5 WARNINGS AND PRECAUTIONS Rebound: Abrupt discontinuation of INOmax may lead to worsening oxygenation and increasing pulmonary artery pressure ( 5.1 ). Methemoglobinemia: Methemoglobin increases with the dose of nitric oxide; following discontinuation or reduction of nitric oxide, methemoglobin levels return to baseline over a period of hours ( 5.2 ). Elevated NO 2 Levels: Monitor NO 2 levels ( 5.3 ). Heart Failure: In patients with pre-existing left ventricular dysfunction, INOmax may increase pulmonary capillary wedge pressure leading to pulmonary edema ( 5.4 ).

5.1 Rebound Pulmonary Hypertension Syndrome following Abrupt Discontinuation Wean from INOmax [see Dosage and Administration (2.2) ]. Abrupt discontinuation of INOmax may lead to worsening oxygenation and increasing pulmonary artery pressure, i.e., Rebound Pulmonary Hypertension Syndrome. Signs and symptoms of Rebound Pulmonary Hypertension Syndrome include hypoxemia, systemic hypotension, bradycardia, and decreased cardiac output. If Rebound Pulmonary Hypertension occurs, reinstate INOmax 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 INOmax; it can take 8 hours or more before steady-state methemoglobin levels are attained. Monitor methemoglobin and adjust the dose of INOmax to optimize oxygenation. If methemoglobin levels do not resolve with decrease in dose or discontinuation of INOmax, 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 3 ppm when measured in the breathing circuit, then the delivery system should be assessed in accordance with the Nitric Oxide Delivery System O&M Manual troubleshooting section, and the NO 2 analyzer should be recalibrated. The dose of INOmax and/or FiO 2 should be adjusted as appropriate.

5.4 Worsening Heart Failure Patients with left ventricular dysfunction treated with INOmax may experience pulmonary edema, increased pulmonary capillary wedge pressure, worsening of left ventricular dysfunction, systemic hypotension, bradycardia and cardiac arrest. Discontinue INOmax while providing symptomatic care.

Nitric oxide donor compounds may increase the risk of developing methemoglobinemia ( 7 ).

7.1 Nitric Oxide Donor Agents Nitric oxide donor agents such as prilocaine, sodium nitroprusside and nitroglycerine may increase the risk of developing methemoglobinemia.

The following adverse reactions are discussed elsewhere in the label; Hypoxemia [see Warnings and Precautions (5.2) ] Worsening Heart Failure [see Warnings and Precautions (5.4) ] The most common adverse reaction is hypotension. ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact INO Therapeutics at 1-877-566-9466 and http://www.inomax.com/ or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 adverse reaction information from the clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Controlled studies have included 325 patients on INOmax doses of 5 to 80 ppm and 251 patients on placebo. Total mortality in the pooled trials was 11% on placebo and 9% on INOmax, a result adequate to exclude INOmax mortality being more than 40% worse than placebo. In both the NINOS and CINRGI studies, the duration of hospitalization was similar in INOmax and placebo-treated groups. From all controlled studies, at least 6 months of follow-up is available for 278 patients who received INOmax and 212 patients who received placebo. Among these patients, there was no evidence of an adverse effect of treatment on the need for rehospitalization, special medical services, pulmonary disease, or 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 INOmax than on placebo) was hypotension (14% vs. 11%).

6.2 Post-Marketing 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.

Overdosage with INOmax is manifest by elevations in methemoglobin and pulmonary toxicities associated with inspired NO 2 . Elevated NO 2 may cause acute lung injury. Elevations in methemoglobin reduce the oxygen delivery capacity of the circulation. In clinical studies, NO 2 levels >3 ppm or methemoglobin levels >7% were treated by reducing the dose of, or discontinuing, INOmax. Methemoglobinemia that does not resolve after reduction or discontinuation of therapy can be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon the clinical situation.

8.4 Pediatric Use The safety and efficacy of nitric oxide for inhalation has been demonstrated in term and near-term neonates with hypoxic respiratory failure associated with evidence of pulmonary hypertension [see Clinical Studies (14.1) ]. Additional studies conducted in premature neonates for the prevention of bronchopulmonary dysplasia have not demonstrated substantial evidence of efficacy [see Clinical Studies (14.3) ]. No information about its effectiveness in other age populations is available.

8.5 Geriatric Use Nitric oxide is not indicated for use in the adult population.

The safety and efficacy of nitric oxide for inhalation has been demonstrated in term and near-term neonates with hypoxic respiratory failure associated with evidence of pulmonary hypertension [see Clinical Studies (14.1) ]. Additional studies conducted in premature neonates for the prevention of bronchopulmonary dysplasia have not demonstrated substantial evidence of efficacy [see Clinical Studies (14.3) ]. No information about its effectiveness in other age populations is available.

Nitric oxide is not indicated for use in the adult population.

INOmax (nitric oxide gas) is a drug administered by inhalation. Nitric oxide, the active substance in INOmax, is a pulmonary vasodilator. INOmax 800 ppm is a gaseous blend of nitric oxide (0.08%) and nitrogen (99.92%). INOmax 4,880™ ppm is a gaseous blend of nitric oxide (0.488%) and nitrogen (99.51%). INOmax 800 ppm is supplied in aluminum cylinders as a compressed gas under high pressure (2,000 pounds per square inch [psi]). INOmax 4,880 ppm is supplied in aluminum cylinders as a compressed gas under high pressure (3,000 psi). The structural formula of nitric oxide (NO) is shown below: Chemical Structure

12.1 Mechanism of Action Nitric oxide relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then leads to vasodilation. When inhaled, nitric oxide selectively dilates the pulmonary vasculature, and because of efficient scavenging by hemoglobin, has minimal effect on the systemic vasculature. INOmax appears to increase the partial pressure of arterial oxygen (PaO 2 ) 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.

12.2 Pharmacodynamics 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 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 INOmax are shown in Figure 1. Figure 1: Methemoglobin Concentration-Time Profiles Neonates Inhaling 0, 5, 20 or 80 ppm INOmax 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 INOmax groups but reached approximately 5% in the 80 ppm INOmax 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.

Nitric oxide relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then leads to vasodilation. When inhaled, nitric oxide selectively dilates the pulmonary vasculature, and because of efficient scavenging by hemoglobin, has minimal effect on the systemic vasculature. INOmax appears to increase the partial pressure of arterial oxygen (PaO 2 ) 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 PaO 2 ).

The pharmacokinetics of nitric oxide has been studied in adults.

, Mutagenesis, Impairment of Fertility No evidence of a carcinogenic effect was apparent, at inhalation exposures up to the recommended dose (20 ppm), in rats for 20 hr/day for up to two years. Higher exposures have not been investigated. Nitric oxide has demonstrated genotoxicity in Salmonella (Ames Test), human lymphocytes, and after in vivo exposure in rats. There are no animal or human studies to evaluate nitric oxide for effects on fertility.

Store at 25°C (77°F) with excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. All regulations concerning handling of pressure vessels must be followed. Protect the cylinders from shocks, falls, oxidizing and flammable materials, moisture, and sources of heat or ignition. INOmax MR conditional labeled cylinders (i.e., size 88 aluminum cylinder) may be used at 100 gauss or less. Use of any other cylinders (e.g., size D or 0.4 liter aluminum cylinder) may create a projectile hazard.