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Overview
Nitric oxide is a vasodilator that is FDA approved for the treatment of treatment of hypoxic respiratory failure. Common adverse reactions include hypotension, drug withdrawal, methemoglobinemia, hypoxemia.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Nitric oxide FDA-Labeled Indications and Dosage (Adult) in the drug label.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Nitric oxide in adult patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitric oxide in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Treatment of Hypoxic Respiratory Failure
Nitric oxide is a vasodilator, which, in conjunction with ventilatory support and other appropriate agents, is indicated for the treatment of term and near-term (>34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation.
Utilize additional therapies to maximize oxygen delivery with validated ventilation systems. In patients with collapsed alveoli, additional therapies might include surfactant and high-frequency oscillatory ventilation.
The safety and effectiveness of INOmax have been established in a population receiving other therapies for hypoxic respiratory failure, including vasodilators, intravenous fluids, bicarbonate therapy, and mechanical ventilation. Different dose regimens for nitric oxide were used in the clinical studies.
Monitor for PaO2, methemoglobin, and inspired NO2 during INOmax administration.
To ensure safe and effective administration of INOmax to avoid adverse events associated with nitric oxide or NO2, administration of INOmax should only be performed by a health care professional who has completed and maintained training on the safe and effective use of a Nitric Oxide Delivery System provided by the manufacturer of the delivery system and the drug.
Dosage
Term and near-term neonates with hypoxic respiratory failure
The recommended dose of INOmax is 20 ppm. Treatment should be maintained up to 14 days or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from INOmax therapy.
As the risk of methemoglobinemia and elevated NO2 levels increases significantly when INOmax is administered at doses >20 ppm; doses above this level are not recommended.
Administration
Methemoglobin should be measured within 4-8 hours after initiation of treatment with INOmax and periodically throughout treatment.
Nitric Oxide Delivery Systems
INOmax must be administered using the INOmax DSIR®, INOmax® DS, or INOvent® Nitric Oxide Delivery Systems, which deliver operator-determined concentrations of nitric oxide in conjunction with a ventilator or breathing gas administration system after dilution with an oxygen/air mixture. A Nitric Oxide Delivery System includes a nitric oxide administration apparatus, a nitric oxide gas analyzer and a nitrogen dioxide gas analyzer. Failure to calibrate the Nitric Oxide Delivery System could result in under- or over- dosing of nitric oxide.
To address potential power failure, keep available a backup battery power supply. To address potential system failure, keep available an independent reserve nitric oxide delivery system. Failure to transition to a reserve nitric oxide delivery system can result in abrupt or prolonged discontinuation of nitric oxide.
Training in Administration
The user of INOmax and Nitric Oxide Delivery Systems must complete a comprehensive training program for health care professionals provided by the delivery system and drug manufacturers.
Health professional staff that administers nitric oxide therapy have access to supplier-provided 24 hour/365 days per year technical support on the delivery and administration of INOmax.
Weaning and Discontinuation
Abrupt discontinuation of INOmax may lead to increasing pulmonary artery pressure (PAP) and worsening oxygenation even in neonates with no apparent response to nitric oxide for inhalation. To wean INOmax, downtitrate in several steps, pausing several hours at each step to monitor for hypoxemia.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Neonatal respiratory failure - Perinatal hypoxia - Pulmonary hypertension: neonates (greater than 34 wk gestation): 20 parts per million (ppm) via INHALATION for up to 14 days or until resolution of oxygen desaturation.
Right-sided heart failure, acute, After implantation of left ventricular assist device (LVAD) in patients with reversible pulmonary hypertension.
Contraindications
It is contraindicated in the treatment of neonates known to be dependent on right-to-left shunting of blood.
Warnings
Rebound Pulmonary Hypertension Syndrome following Abrupt Discontinuation
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 the concentration of NO2 in the breathing circuit exceeds 0.5 ppm, decrease the dose of INOmax.
If there is an unexpected change in NO2 concentration, 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.
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.
Adverse Reactions
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.
Clinical Trials Experience
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%).
Postmarketing Experience
Accidental Exposure
Based upon post-marketing experience, accidental exposure to nitric oxide for inhalation in hospital staff has been associated with chest discomfort, dizziness, dry throat, dyspnea, and headache.
Drug Interactions
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. INOmax has been administered with dopamine, dobutamine, steroids, surfactant, and high-frequency ventilation.
Although there are no study 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. An association between prilocaine and an increased risk of methemoglobinemia, particularly in infants, has specifically been described in a literature case report. This risk is present whether the drugs are administered as oral, parenteral, or topical formulations.
Animal reproduction studies have not been conducted with INOmax. It is not known if INOmax can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. INOmax is not intended for adults.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nitric oxide in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Nitric oxide during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Nitric oxide with respect to nursing mothers.
Pediatric Use
There is no FDA guidance on the use of Nitric oxide with respect to pediatric patients.
Geriatic Use
There is no FDA guidance on the use of Nitric oxide with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Nitric oxide with respect to specific gender populations.
Race
There is no FDA guidance on the use of Nitric oxide with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Nitric oxide in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Nitric oxide in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nitric oxide in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Nitric oxide in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Intravenous
Monitoring
There is limited information regarding Monitoring of Nitric oxide in the drug label.
Description
IV Compatibility
There is limited information regarding IV Compatibility of Nitric oxide in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
Description
Management
Description
Chronic Overdose
There is limited information regarding Chronic Overdose of Nitric oxide in the drug label.
