Side Effects of Inomax (nitric oxide gas)

Inomax (nitric oxide gas) is a vasodilator indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term (more than 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.

Common side effects of Inomax include low blood pressure (hypotension).

Serious side effects of Inomax include

• rebound pulmonary hypertension syndrome following abrupt discontinuation (symptoms include low blood oxygen, systemic low blood pressure, slow heart rate, and decreased cardiac output),
• low blood oxygen (hypoxemia) from methemoglobinemia,
• airway injury from nitrogen dioxide, and
• worsening heart failure (pulmonary edema, increased pulmonary capillary wedge pressure, worsening of left ventricular dysfunction, systemic hypotension, slow heart rate, and cardiac arrest). 

Drug interactions of Inomax include nitric oxide donor compounds, which may increase the risk of developing methemoglobinemia. 

It is unknown if Inomax can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. 

Inomax is not indicated for use in adults. 

It is not known whether nitric oxide is excreted in human milk. Inomax is not indicated for use in the adult population, including breastfeeding mothers. 

Rebound Pulmonary Hypertension Syndrome following Abrupt Discontinuation

Wean from Inomax. 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.

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.

Airway Injury from Nitrogen Dioxide

• Nitrogen dioxide (NO2) forms in gas mixtures containing NO and O2. Nitrogen dioxide may cause airway inflammation and damage to lung tissues.
• If there is an unexpected change in NO2 concentration, or if the NO2 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 NO2 analyzer should be recalibrated. The dose of Inomax and/or FiO2 should be adjusted as appropriate.

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.
• The most common adverse reaction is hypotension.

The following adverse reactions are discussed elsewhere in the label;

• Hypoxemia
• Worsening Heart Failure

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%).

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.

Nitric Oxide Donor Agents

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