NITRIC: 3,068 Adverse Event Reports & Safety Profile

GENOSYL (nitric oxide) is administered by inhalation. Nitric oxide is a pulmonary vasodilator. Nitric oxide is generated from liquid dinitrogen tetroxide (N 2 O 4 ) by the cassette in the GENOSYL Delivery System. Upon initiation of GENOSYL Delivery System, the liquid N 2 O 4 is heated and the equilibrium shifts to nitrogen dioxide (NO 2 ) gas. The NO 2 is then converted into nitric oxide (NO) using the antioxidant cartridges, and nitric oxide is delivered to the patient by means of a ventilator or a nasal cannula. The amount of nitric oxide administered to the patient is set by controlling the temperature of the N 2 O 4 liquid module, which controls the pressure inside the liquid module, which in turn controls the mass of NO 2 that is sent to the primary cartridges, and hence the mass of nitric oxide. The mass flow of nitric oxide, together with the air from the pump, control the nitric oxide concentration. A nitric oxide sensor monitors the nitric oxide in the patient line.

Genosyl

Delivery System is designed to deliver a controlled level of nitric oxide blended with breathing air or oxygen-enriched breathing air. The GENOSYL Delivery System controls the flow of nitric oxide mixed with air delivered to the patient. The structural formula of nitric oxide (NO) is shown below: Chemical Structure

INDICATIONS AND USAGE Noxivent™ 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.

1.

Indications And Usage

Noxivent™ 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.

AND ADMINISTRATION 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 GENOSYL 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 GENOSYL therapy. Doses greater than 20 ppm are not recommended <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>.

2.2 Administration Nitric Oxide Delivery System GENOSYL must be administered using a calibrated GENOSYL Delivery System. Only validated ventilator systems should be used in conjunction with GENOSYL <span class="opacity-50 text-xs">[see Description (11) ]</span>. Consult the GENOSYL Delivery System Operator&apos;s Manual or call 1-877-337-4118 or visit www.vero-biotech.com for needed information on training and technical 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.

CONTRAINDICATIONS Neonates dependent on right-to-left shunting of blood ( 4 ).

4.

Contraindications

Noxivent™ is contraindicated in neonates dependent on right-to-left shunting of blood.

REACTIONS 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 Vero Biotech at 1-877-337-4118 and http://www.vero-biotech.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 nitric oxide doses of 5 to 80 ppm and 251 patients 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 (&gt;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.

WARNINGS AND PRECAUTIONS Rebound: Abrupt discontinuation of Noxivent™ 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, Noxivent™ may increase pulmonary capillary wedge pressure leading to pulmonary edema ( 5.4 ).

5. WARNINGS AND PRECAUTIONS

5.1 Rebound Pulmonary Hypertension Syndrome following Abrupt Discontinuation Wean from Noxivent™ <span class="opacity-50 text-xs">[see Dosage and Administration (2.2 )]</span>. Abrupt discontinuation of Noxivent™ 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 Noxivent™ 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 Noxivent™; it can take 8 hours or more before steady-state methemoglobin levels are attained. Monitor methemoglobin and adjust the dose of Noxivent™ to optimize oxygenation. If methemoglobin levels do not resolve with decrease in dose or discontinuation of Noxivent™, additional therapy may be warranted to treat methemoglobinemia <span class="opacity-50 text-xs">[see Overdosage (10 )]</span>.

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&amp;M Manual troubleshooting section, and the NO 2 analyzer should be recalibrated. The dose of Noxivent™ and/or FiO 2 should be adjusted as appropriate.

5.4 Worsening Heart Failure Patients with left ventricular dysfunction treated with Noxivent™ may experience pulmonary edema, increased pulmonary capillary wedge pressure, worsening of left ventricular dysfunction, systemic hypotension, bradycardia and cardiac arrest.

Discontinue

Noxivent™ while providing symptomatic care.

DRUG INTERACTIONS Nitric oxide donor compounds may increase the risk of developing methemoglobinemia ( 7 ). Revised: 08/2023

7. DRUG INTERACTIONS

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